Cycloalkylamines as monoamine reuptake inhibitors

ABSTRACT

The invention relates to novel cyclohexylamine derivatives and their use in the treatment and/or prevention of central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/688,474 filed on Jan. 15, 2010, which is a continuation of U.S.application Ser. No. 11/649,927, filed on Jan. 5, 2007, which claimspriority to U.S. Provisional Patent Application No. 60/756,550 filedJan. 6, 2006, the entire contents of each of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The invention relates to compounds and compositions for the treatment ofcentral nervous system (CNS) disorders.

BACKGROUND OF THE INVENTION

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion, mood, or affect. These disorders may vary inseverity of symptoms, duration, and functional impairment. Psychiatricdisorders afflict millions of people worldwide resulting in tremendoushuman suffering and economic burden due to lost productivity anddependent care.

Over the past several decades, the use of pharmacological agents totreat psychiatric disorders has greatly increased, largely due toresearch advances in both neuroscience and molecular biology. Inaddition, chemists have become increasingly sophisticated at creatingchemical compounds that are more effective therapeutic agents with fewerside effects, targeted to correct the biochemical alterations thataccompany mental disorders.

Yet, despite the many advances that have occurred, many psychiatricdiseases remain untreated or inadequately treated with currentpharmaceutical agents. In addition, many of the current agents interactwith molecular targets not involved with the psychiatric disease. Thisindiscriminate binding can result in side effects that can greatlyinfluence the overall outcome of therapy. In some cases the side effectsare so severe that discontinuation of therapy is required.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. It is characterized by apersistently low mood or diminished interests in one's surroundings,accompanied by at least one of the following symptoms: reduced energyand motivation, difficulty concentrating, altered sleep and appetite,and at times, suicidal ideation (American Psychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, ed. 4.Washington, American Psychiatric Association, 1994). Major depression isassociated with high rates of morbidity and mortality, with suiciderates of 10-25% (Kaplan H I, Sadock B J (eds): Synopsis of Psychiatry.Baltimore, Williams & Wilkins, 1998, p. 866). The compounds of theinvention may also be used to reduce fatigue commonly associated withdepression (see, for example, “Bupropion augmentation in the treatmentof chronic fatigue syndrome with coexistent major depression episode”Schonfeldt-Lecuona et al., Pharmacopsychiatry 39(4):152-4, 2006;“Dysthymia: clinical picture, extent of overlap with chronic fatiguesyndrome, neuropharmacological considerations, and new therapeuticvistas” Brunello et al., J. Affect. Disord. 52(1-3):275-90, 1999;“Chronic fatigue syndrome and seasonal affective disorder: comorbidity,diagnostic overlap, and implications for treatment” Terman et al., Am.J. Med. 105(3A):115S-124S, 1998.).

Depression is believed to result from dysfunction in the noradrenergicor serotonergic systems, more specifically, from a deficiency of certainneurotransmitters (NTs) at functionally important adrenergic orserotonergic receptors.

Neurotransmitters produce their effects as a consequence of interactionswith specific receptors. Neurotransmitters, including norepinephrine(NE) and/or serotonin (5-hydroxytryptamine, or 5-HT), are synthesized inbrain neurons and stored in vesicles. Upon a nerve impulse, NTs arereleased into the synaptic cleft, where they interact with variouspostsynaptic receptors. Regional deficiencies in the synaptic levels of5-HT and/or NE are believed to be involved in the etiology ofdepression, wakefulness, and attention.

Norepinephrine is involved in regulating arousal, dreaming, and moods.Norepinephrine can also contribute to the regulation of blood pressure,by constricting blood vessels and increasing heart rate.

Serotonin (5-HT) is implicated in the etiology or treatment of variousdisorders. The most widely studied effects of 5-HT are those on the CNS.The functions of 5-HT are numerous and include control of appetite,sleep, memory and learning, temperature regulation, mood, behavior(including sexual and hallucinogenic behavior), cardiovascular function,smooth muscle contraction, and endocrine regulation. Peripherally, 5-HTappears to play a major role in platelet homeostasis and motility of theGI tract. The actions of 5-HT are terminated by three major mechanisms:diffusion; metabolism; and reuptake. The major mechanism by which theaction of 5-HT is terminated is by reuptake through presynapticmembranes. After 5-HT acts on its various postsynaptic receptors, it isremoved from the synaptic cleft back into the nerve terminal through anuptake mechanism involving a specific membrane transporter in a mannersimilar to that of other biogenic amines. Agents that selectivelyinhibit this uptake increase the concentration of 5-HT at thepostsynaptic receptors and have been found to be useful in treatingvarious psychiatric disorders, particularly depression.

Approaches to the treatment of depression over the years have involvedthe use of agents that increase the levels of NE and 5-HT, either byinhibiting their metabolism (e.g., monoamine oxidase inhibitors) orreuptake (e.g., tricyclic antidepressants or selective serotoninreuptake inhibitors (SSRIs)).

There are more than twenty approved antidepressant drugs available inthe United States. The classical tricyclic antidepressants (TCAs)currently available block primarily the uptake of NE and also, tovarying degrees, the uptake of 5-HT, depending on whether they aresecondary or tertiary amines. Tertiary amines such as imipramine andamitriptyline are more selective inhibitors of the uptake of 5-HT thanof catecholamines, compared with secondary amines such as desipramine.

Selective serotonin reuptake inhibitors have been investigated aspotential antidepressants. Fluoxetine (PROZAC®), sertraline (ZOLOFT®),and paroxetine (PAXIL®) are three examples of SSRIs currently on theU.S. market. These agents do not appear to possess greater efficacy thanthe TCAs, nor do they generally possess a faster onset of action;however, they do have the advantage of causing less side-effects. Ofthese three SSRIs, paroxetine is the most potent inhibitor of 5-HTuptake, fluoxetine the least. Sertaline is the most selective for 5-HTversus NE uptake, fluoxetine the least selective. Fluoxetine andsertraline produce active metabolites, while paroxetine is metabolizedto inactive metabolites. The SSRIs, in general, affect only the uptakeof serotonin and display little or no affinity for various receptorsystems including muscarinic, adrenergic, dopamine, and histaminereceptors.

In addition to treating depression, several other potential therapeuticapplications for SSRIs have been investigated. They include treatment ofAlzheimer's disease, aggressive behavior, premenstrual syndrome,diabetic neuropathy, chronic pain, fibromyalgia, and alcohol abuse. Forexample, fluoxetine is approved for the treatment ofobsessive-compulsive disorder (OCD). Of particular significance is theobservation that 5-HT reduces food consumption by increasingmeal-induced satiety and reducing hunger, without producing thebehavioral effects of abuse liability associated with amphetamine-likedrugs. Thus, there is interest in the use of SSRIs in the treatment ofobesity.

Venlafaxine (EFFEXOR®) is a dual-reuptake antidepressant that differsfrom the classical TCAs and the SSRIs chemically and pharmacologicallyin that it acts as a potent inhibitor of both 5-HT and NE uptake.Neither venlafaxine nor its major metabolite have a significant affinityfor adrenergic alpha-1 receptors. Venlafaxine possesses an efficacyequivalent to that of the TCAs, and a benign side effect profile similarto those of the SSRIs.

Dopamine is hypothesized to play a major role in psychosis and certainneurodegenerative diseases, such as Parkinson's disease, where adeficiency in dopaminergic neurons is believed to be the underlyingpathology. Dopamine affects brain processes that control movement,emotional response, and ability to experience pleasure and pain.Regulation of DA plays a crucial role in our mental and physical health.Certain drugs increase DA concentrations by preventing DA reuptake,leaving more DA in the synapse. An example is methylphenidate(RITALIN®), used therapeutically to treat childhood hyperkinesias andsymptoms of schizophrenia. Dopamine abnormalities are believed tounderlie some of the core attentional abnormalities seen in acuteschizophrenics.

A therapeutic lag is associated with the use of these drugs. Patientsmust take a drug for at least three (3) weeks before achievingclinically meaningful symptom relief. Furthermore, a significant numberof patients do not respond to current therapies at all. For example, itis currently estimated that up to thirty percent (30%) of clinicallydiagnosed cases of depression are resistant to all forms of drugtherapy.

SUMMARY OF THE INVENTION

The present invention relates to novel cycloalkylamines and saltsthereof. It further relates to novel pharmaceutical compositions, andtheir use in the treatment of CNS disorders such as depression (e.g.,major depressive disorder, bipolar disorder), fibromyalgia, pain (e.g.,neuropathic pain), sleep apnea, attention deficit disorder (ADD),attention deficit hyperactivity disorder (ADHD), restless leg syndrome,schizophrenia, anxiety, obsessive compulsive disorder, posttraumaticstress disorder, seasonal affective disorder (SAD), premenstrualdysphoria as well as neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease).

Hence, in a first aspect the invention provides a compound having astructure according to Formula (I):

In Formula (I), n is an integer from 0 to 2; s is an integer from 1 to3. The integer m is selected from 0 to 12. When n is 0, m is preferablynot greater than 8; when n is 1, m is preferably not greater than 10. Aris a member selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl and a fusedring system.

Each X is an independently selected alkyl group substituent. In anexemplary embodiment, each X is a member independently selected from thegroup consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵,C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein each R⁵, R⁶ and R⁷ is a member independentlyselected from the group consisting of H, acyl, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl, wherein two of R⁵, R⁶ and R⁷, together with the atoms towhich they are attached, are optionally joined to form a 3- to7-membered ring.

Each R¹ and R² is an independently selected alkyl group substituent. Inan exemplary embodiment, each R¹ and R² is a member independentlyselected from the group consisting of H, halogen, CN, CF₃, OR⁸,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein R⁸ is a member selected from the groupconsisting of H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

R³ and R⁴ are members independently selected from the group consistingof H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, ═N═N, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl andsubstituted or unsubstituted heterocycloalkyl. When one member of R³ andR⁴ is ═N═N, the other member is preferably not present. R⁹ is a memberselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl andsubstituted or unsubstituted heterocycloalkyl.

At least two of R¹, R², R³, R⁴ and any of the substituents X, togetherwith the atoms to which they are attached, are optionally joined to forma 3- to 7-membered ring.

Any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, and enantiomericallypure form of the above described compounds falls within the scope of theinvention.

In a second aspect, the invention provides a pharmaceutical compositionincluding a compound of the invention or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

In a third aspect, the invention provides a method of inhibiting bindingof a monoamine transporter ligand to a monoamine transporter, such asserotonin transporter, dopamine transporter and norepinephrinetransporter. The method includes contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment themonoamine transporter ligand is a monoamine, such as serotonin, dopamineand norepinephrine.

In a fourth aspect, the invention provides a method of inhibiting theactivity of at least one monoamine transporter, such as serotonintransporter, dopamine transporter and norepinephrine transporter. Themethod includes contacting the monoamine transporter and a compound ofthe invention.

In another aspect, the invention provides a method of inhibiting uptakeof at least one monoamine, such as serotonin, dopamine andnorepinephrine, by a cell. The method includes contacting the cell witha compound of the invention. In an exemplary embodiment, the cell is abrain cell, such as a neuronal cell or a glial cell.

In yet another aspect, the invention provides a method of treatingdepression by inhibiting the activity at least one monoaminetransporter. The method includes administering to a mammalian subject acompound of the invention. In a preferred embodiment, the compound ofthe invention inhibits the activity of at least two different monoaminetransporters. In another preferred embodiment, the mammalian subject isa human.

In a further aspect, the invention provides a method of treating acentral nervous system disorder. The method includes administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention or a pharmaceutically acceptable salt or solvatethereof. In a preferred embodiment, the subject is a human.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, is also meant to include those derivatives of alkyldefined in more detail below, such as “heteroalkyl.” Alkyl groups thatare limited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂₅—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.Similarly, the term “heteroalkylene” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —CO₂R′—represents both —C(O)OR′ and —OC(O)R′.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, S, Si and B,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. A heteroaryl group can beattached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxyl)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups including carbon atoms boundto groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″and R″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)-D-, wherein A and D are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X″—(CR″R′″)_(d)—, where s and d are independently integersof from 0 to 3, and X″ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen or substituted or unsubstituted(C₁-C₆)alkyl.

As used herein, the term “acyl” describes a substituent containing acarbonyl residue, C(O)R. Exemplary species for R include H, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl.

As used herein, the term “fused ring system” means at least two rings,wherein each ring has at least 2 atoms in common with another ring.“Fused ring systems” may include aromatic as well as non aromatic rings.Examples of “fused ring systems” are naphthalenes, indoles, quinolines,chromenes and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S), silicon (Si) and boron (B).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl groups.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, or composition comprising a compound of thepresent invention which is effective for producing some desiredtherapeutic effect (e.g., by inhibiting uptake of a monoamine from thesynaptic cleft of a mammal, thereby modulating the biologicalconsequences of that pathway in the treated organism) at a reasonablebenefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein meansany pharmaceutically acceptable material, which may be liquid or solid.Exemplary carriers include vehicles, diluents, additives, liquid andsolid fillers, excipients, solvents, solvent encapsulating materials.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids. The term “pharmaceutically acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, sulfamate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, tosylate, citrate, maleate, ascorbate, palmitate, fumarate,succinate, tartrate, napthylate, mesylate, hydroxymaleate,phenylacetate, glutamate, glucoheptonate, salicyclate, sulfanilate,2-acetoxybenzoate, methanesulfonate, ethane disulfonate, oxalate,isothionate, lactobionate, and laurylsulphonate salts and the like. See,for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.

The term “pharmaceutically acceptable salts” includes salts of theactive compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66: 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention. “Compound or a pharmaceutically acceptable salt orsolvate of a compound” intends the inclusive meaning of “or”, in that amaterial that is both a salt and a solvate is encompassed.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. Optically active (R)- and (S)-isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. Likewise, all tautomeric formsare also intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62: 114-120 (1985): solid and broken wedges are used todenote the absolute configuration of a chiral element; wavy linesindicate disavowal of any stereochemical implication which the bond itrepresents could generate; solid and broken bold lines are geometricdescriptors indicating the relative configuration shown but not implyingany absolute stereochemistry; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess,” those with atleast two stereocenters are referred to as being present in“diastereomeric excess.”

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “monoamine transporter ligand” refers to any compound, whichbinds to a monoamine transporter. Ligands include endogenous monoamines,which are the natural ligands for a given monoamine transporter as wellas drug molecules and other compounds, such as synthetic molecules knownto bind to a particular monoamine transporter. In one example, theligand includes a radioisotope, such as tritium or is otherwise (e.g.,fluorescently) labeled. It is within the abilities of a skilled personto select an appropriate ligand for a given monoamine transporter. Forexample, known ligands for the dopamine transporter include dopamine andWIN35428, known ligands for the serotonin transporter include5-hydroxytryptamine (serotonin) and citalopram, and ligands for thenorepinephrine transporter include norepinephrine and nisoxetine.

The term “central nervous system disorder” refers to any abnormalcondition of the central nervous system of a mammal. Central nervoussystem disorder includes neurodegenerative diseases such Alzheimer'sdisease and Parkinson's disease, neuropsychiatric diseases (e.g.schizophrenia), anxieties, sleep disorders, depression, dementias,movement disorders, psychoses, alcoholism, post-traumatic stressdisorder and the like. “Central nervous system disorder” also includesany condition associated with the disorder, such as loss of memoryand/or loss of cognition. For instance, a method of treating aneurodegenerative disease would also include treating or preventing lossof neuronal function characteristic of such disease. “Central nervoussystem disorder” also includes any disease or condition that isimplicated, at least in part, in monoamine (e.g., norepinephrine)signaling pathways (e.g., cardiovascular disease).

The term “pain” refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety). “Pain” is also meant toinclude mixed etiology pain, dual mechanism pain, allodynia, causalgia,central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.

The term “depression” includes all forms of depression, which includemajor depressive disorder (MDD), bipolar disorder, seasonal affectivedisorder (SAD) and dysthymia. “Major depressive disorder” is used hereininterchangeably with “unipolar depression” and “major depression”.“Depression” also includes any condition commonly associated withdepression, such as all forms of fatigue (e.g., chronic fatiguesyndrome) and cognitive deficits.

II. Introduction

One strategy to develop effective therapies is the use of broad spectrumantidepressants that simultaneously inhibit the reuptake of more thanone biogenic amine, such as serotonin (5-HT), norepinephrine (NE) anddopamnine (DA). The rationale for this approach is based upon clinicaland preclinical evidence showing that deficiencies in dopaminergicfunction can be correlated with anhedonia, which is a core symptom ofdepression. Baldessarini, R. J., “Drugs and the Treatment of PsychiatricDisorders: Depression and Mania”, in Goodman and Gilman's ThePharmacological Basis of Therapeutics 431-459 (9^(th) ed 1996) Hardmanet al. eds.

An advantage of the compounds and compositions of the present inventionis their ability to increase synaptic availability of at least twoneurotransmitters (e.g, NE, 5-HT and DA) by inhibiting their (re)uptakefrom the synaptic cleft. Skolnick and coworkers report on a body ofpreclinical evidence suggesting that the therapeutic profile of anantidepressant concurrently increasing the synaptic availability of DA,NE and 5-HT will differ from a compound inhibiting only NE and/or 5-HT.Skolnick, P. et al., “Antidepressant-like actions of DOV-21,947: a“triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461, 103.

For example, Skolnick and coworkers have reported that a compound, DOV21,947 ((+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane), inhibitsthe reuptake of serotonin, norepinephrine, and dopamine in humanembryonic kidney (HEK293) cells expressing the corresponding humanrecombinant transporters (IC₅₀ values of 12, 23 and 96 nM,respectively). Skolnick, P. et al., “Antidepressant-like actions ofDOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461,99. In addition, DOV 21,947 reduces the duration of immobility in theforced swim test (in rats) and also produces a dose-dependent reductionin immobility in the tail suspension test. Additional evidence can befound in preclinical data for new triple reuptake inhibitors such as DOV21,947 in, e.g., U.S. Pat. No. 6,372,919, wherein DOV 21,947 wasdisclosed as having a significantly greater affinity for thenorepinephrine and serotonin uptake sites than the racemic compound,(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.

Taken together, the preclinical data for compounds such as DOV 21,947indicate that dual or triple reuptake inhibitors may hold potential asnovel treatments for depression in the clinic.

III. Compositions A. Cycloalkyl Amines

In a first aspect, the invention provides a compound having a structureaccording to Formula (I):

In Formula (I), n is an integer from 0 to 2. Hence, in one embodiment,the invention provides cyclopentyl-, cyclohexyl- and cycloheptylamines.The integer s is selected from 0 to 3, preferably from 1 to 2. In aparticularly preferred embodiment, s is 1. The integer m is selectedfrom 0 to 12. When n is 0, m is preferably not greater than 8; when n is1, m is preferably not greater than 10. Ar is a member selected from thegroup consisting of substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and a fused ring system.

Each X is a member independently selected from an alkyl groupsubstituent. In an exemplary embodiment, each X is a memberindependently selected from the group consisting of H, halogen, CN, CF₃,OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷,NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl. Each R⁵, R⁶ and R⁷ is a member independently selectedfrom the group consisting of H, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, whereintwo of R⁵, R⁶ and R⁷, together with the atoms to which they areattached, are optionally joined to form a 3- to 7-membered ring.

Each R¹ and R² is an independently selected alkyl group substituent. Inan exemplary embodiment, each R¹ and R² is a member independentlyselected from the group consisting of H, halogen, CN, CF₃, Ole,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein R⁸ is a member selected from the groupconsisting of H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

In one embodiment, R³ and R⁴ are members independently selected from thegroup consisting of H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, ═N═N, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl. When onemember of R³ and R⁴ is ═N═N, the other member is preferably not present.R⁹ is a member selected from the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl.

At least two of R¹, R², R³, R⁴ and any substituent X, together with theatoms to which they are attached, are optionally joined to form a 3- to7-membered ring. In an exemplary embodiment, two substituents X,together with the atoms to which they are attached, are optionallyjoined to form a 3- to 7-membered ring. In another exemplary embodiment,R³ and R⁴ are joined to form a ring, such as a morpholine,N-methyl-piperazine and the like. In another exemplary embodiment, R¹and R³ are joined to form a ring, such as a pyrrolidine ring. In yetanother exemplary embodiment, at least one of R′, R², R³ and R⁴ isoptionally joined with the Ar group or a substituent on the Ar group toform a 5- to 7-membered ring. An exemplary structure, in which Ar-ssubstituted phenyl and R³ is joined with Ar to form a 6-membered ring isprovided below:

wherein Y and Z are as defined below.

In an especially preferred embodiment, the integer s in Formula (I)is 1. Exemplary compounds according to this embodiment have a Formula,which is a member selected from Formula (II) and Formula (III):

In an exemplary embodiment, the cycloalkyl ring is mono- ordisubstituted at either the 2-, 3-, or 4-position. Exemplary compoundsaccording to this embodiment have a Formula, which is a member selectedfrom the group consisting of:

wherein X¹ and X² are alkyl group substituents. In an exemplaryembodiment, X¹ and X² are each defined as the substituent X, above. Inanother exemplary embodiment, X¹ and X² are members independentlyselected from the group consisting of H, OR⁵, SR⁵, halogen, CN, CF₃,S(O)₂R⁵, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, acyl, substituted orunsubstituted C₁-C₄ alkyl and substituted or unsubstituted C₁-C₄heteroalkyl, wherein at least two of R¹, R³, R⁴, X¹ and X², togetherwith the atoms to which they are attached, are optionally joined to forma 3- to 7-membered ring.

In a preferred embodiment, X¹ and X² are members independently selectedfrom H, methyl, ethyl, propyl, OR⁵ (e.g., OH, OMe, OEt, OPh), CH₂OR⁵(e.g., CH₂OH), halogen substituted alkyl (e.g., CF₃, CH₂F), halogen(e.g., F or Cl) and CN. In another preferred embodiment, R¹ is a memberselected from H and substituted or unsubstituted C₁-C₄ alkyl. In yetanother preferred embodiment, R³ and R⁴ are members independentlyselected from H, substituted or unsubstituted alkyl and substituted orunsubstituted heteroalkyl, such as substituted or unsubstituted C₁-C₄alkyl or substituted or unsubstituted C₁-C₄ heteroalkyl. In one example,R³ and R⁴, together with the nitrogen atom to which they are attached,are joined to form a 3- to 7-membered ring, such as a morpholine,piperidine, pyrrolidine or N-alkyl-piperazine moiety.

In another embodiment, the compound of the invention includes acyclobutyl ring. An exemplary structure is provided below in Formula(IV):

wherein the integer q is selected from 0 to 6.

Aryl Group Substituent (Ar)

In one embodiment, Ar is a member selected from substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl and a fusedring system. Preferably, Ar is a member selected from substituted orunsubstituted phenyl and substituted or unsubstituted naphthyl,including 1-naphthyl and 2-naphthyl analogs. Hence, in one embodiment,Ar is a member selected from:

wherein Y, Z, Y¹ and Z¹ are members independently selected from arylgroup substituents. In an exemplary embodiment, Y, Z, Y¹ and Z¹ aremembers independently selected from H, halogen, CF₃, CN, OR¹¹, SR¹¹,NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, S(O)₂R¹¹, acyl, C(O)OR¹¹,C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted heterocycloalkyl. Each R¹¹, R¹² and R¹³ is a memberindependently selected from the group consisting of H, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycloalkyl, wherein twoof R¹¹, R¹² and R¹³, together with the atoms to which they are attached,are optionally joined to form a 3- to 7-membered ring.

Two of Y, Z, Y¹ and Z¹, together with the atoms to which they areattached, are optionally joined to form a 5- to 7-membered ring, such asa dioxolyl ring. In another exemplary embodiment, Y, Z, Y¹ and Z¹ aremembers independently selected from the group consisting of H, halogen,CN, halogen substituted C₁-C₄ alkyl (e.g., CF₃) and C₁-C₄ alkoxy (e.g.,OMe, OEt, OCF₃).

In yet another exemplary embodiment, Ar is a 3,4-disubstituted phenylmoiety and has the structure:

In a preferred embodiment, Y and Z, in the structure above, are membersindependently selected from H, halogen, CN, CF₃ and OR¹⁶ (e.g., OMe,OEt, OCF₃). In a particular preferred embodiment, Y and Z are bothhalogen. In an exemplary embodiment, Ar in any of the structures aboveis 3,4-dichlorophenyl.

Exemplary compounds according to the above described embodiments areprovided below:

In an exemplary embodiment, in the structures above, R¹, R³ and R⁴ areindependently selected from H and C₁ to C₄ alkyl (e.g., methyl) and X¹and X² are independently selected from H, OH, OMe, methyl, ethyl, CH₂OH,halogen (e.g., Cl and F), CN and CF₃.

The compounds of the invention include an amine moiety (e.g., a primary,secondary or tertiary amino group) and as such can be converted into asalt form by contacting the compound (e.g., the free base) with an acid.In an exemplary embodiment, the salt form is generated to convert anotherwise oily or viscous compound into a solid substance for easierhandling. In another exemplary embodiment, converting the free base of acompound of the invention into a corresponding salt increases solubilityof the compound in aqueous media, which can effect biologicalcharacteristics, such as bioavailability, pharmacokinetics andpharmacodynamics. Hence, any salt forms, such as pharmaceuticallyacceptable salts, including salts of inorganic acids (e.g.,hydrochloride salts) or organic acids, of the compounds of the inventionare within the scope of the current invention. Also within the scope ofthe invention are any prodrugs of the compounds of the invention. Forexample, R³ and R⁴ can be any group, which is cleavable in vivo toresult in an amine, such as a primary or secondary amine.

In another embodiment, the invention provides synthetic precursors forthe cycloalkylamines of the invention. For example, a large subset ofthe currently provided amines can be synthesized via the correspondingnitrile (e.g., by reduction) or the corresponding aldehyde (e.g., byreductive amination). Thus, the invention provides compounds having astructure selected from the following Formulae:

wherein p is an integer selected from 0 to 2. Ar, R¹, R², X and theintegers m and n are as defined above. In a preferred embodiment p is 0.

In another embodiment, the invention provides cycloalkylamines, whereinthe cycloalkyl ring includes one or more double bonds. Exemplarycompounds are shown below:

wherein the integer r is selected from 0 to 8 and t is selected from 0to 6.

B. Compositions Including Stereoisomers

The compound of the invention can include one or more stereocenter andmay exist in particular geometric or stereoisomeric forms. Compounds canbe chiral, racemic or be present in a composition including one or morestereoisomer. The current invention encompasses any enantiomer,diastereomer, racemic mixtures, enantiomerically enriched mixtures, anddiastereomerically enriched mixture as well as any enantiomerically ordiastereomerically (essentially) pure forms of the compounds of theinvention. The invention contemplates cis- and trans-isomers, (−)- and(+)-enantiomers, (D)-isomers, (L)-isomers, as falling within the scopeof the invention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivatization with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group, such as an amino group, or an acidicfunctional group, such as a carboxyl group, diastereomeric salts may beformed with an appropriate optically active acid or base, followed byresolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

As used herein, the term “enantiomerically enriched” or“diastereomerically enriched” refers to a compound having anenantiomeric excess (ee) or a diastereomeric excess (de) greater thanabout 50%, preferably greater than about 70% and more preferably greaterthan about 90%. In general, higher than about 90% enantiomeric ordiastereomeric purity is particularly preferred, e.g., thosecompositions with greater than about 95%, greater than about 97% andgreater than about 99% ee or de.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess”, those with atleast two stereocenters are referred to as being present in“diastereomeric excess”.

For example, the term “enantiomeric excess” is well known in the art andis defined as:

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingenantiomerically pure. A compound which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% ee.A 90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

Hence, in one embodiment, the invention provides a composition includinga first stereoisomer and at least one additional stereoisomer of acompound of the invention. The first stereoisomer may be present in adiastereomeric or enantiomeric excess of at least about 80%, preferablyat least about 90% and more preferably at least about 95%. In aparticularly preferred embodiment, the first stereoisomer is present ina diastereomeric or enantiomeric excess of at least about 96%, at leastabout 97%, at least about 98%, at least about 99% or at least about99.5%. Enantiomeric or diastereomeric excess may be determined relativeto exactly one other stereoisomer, or may be determined relative to thesum of at least two other stereoisomers. In an exemplary embodiment,enantiomeric or diastereomeric excess is determined relative to allother detectable stereoisomers, which are present in the mixture.Stereoisomers are detectable if a concentration of such stereoisomer inthe analyzed mixture can be determined using common analytical methods,such as chiral HPLC.

C. Synthesis of the Compounds 1. General

Compounds of the invention may be synthesized as a racemic mixture, amixture of cis and trans isomers, or a mixture of two or morediastereomers. Stereoisomers may be separated at an appropriatesynthetic stage, for example, by chiral column chromatography, such asHPLC to give enantiomerically/diastereomerically enriched orenantiomerically or diastereomerically pure forms of the respectivestereoisomers. Cis and trans assignments may be made on the basis of NMRcoupling patterns optionally in conjunction with literature values.Absolute configurations can be determined by synthesis from chiralprecursor of known configuration, or by X-ray crystallographicdetermination using crystallized materials.

Numbering of the positions within the cycloalkyl ring structure is basedon the following Scheme:

Cis- and trans-configurations are defined according to the relativeconfiguration of the amine-bearing side chain and the substituent on thecyclalkyl ring. When more than one substituent is present, the higherorder (IUPAC) substituent is used for the determination of cis- andtrans-configuration. Examples are outlined below:

(a) 2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

(b) 3-(aminomethyl)-3-(3,4-dichlorophenyl)-1-methylcyclohexanol

Compounds of the invention may be synthesized according to Schemes 1 to23, below. It is within the abilities of a person skilled in the art toselect appropriate alternative reagents replacing the exemplary reagentsshown in Schemes 1-23 in order to synthesize a desired compound of theinvention. It is also within the abilities of a skilled artisan to omitor add synthetic steps when necessary. As a non-limiting example, Ar inSchemes 1 to 23 is selected from substituted or unsubstituted phenyl. Inan exemplary embodiment, Ar is 3,4-dichlorophenyl.

2. General Synthesis of Cycloalkylamines

In one embodiment, the compounds of the invention are synthesized fromthe corresponding nitrile C as shown in Scheme 1, below.

Synthesis of the nitrile C and the carboxylic acid intermediate E can,for example, be accomplished as described by Calderon et al., J. Med.Chem. 1994, 37, 2285, which is incorporated herein by reference. Inaddition, the reduction of the nitrile C to the corresponding primaryamine D can be accomplished by borane reduction, for example, asdescribed by Nagarathnam et al., J. Med. Chem. 1998, 41, 5320, which isalso incorporated herein by reference.

Referring to Scheme 1, alkylation of the acetonitrile A withdibromoalkane B (e.g., with NaH in DMSO) gives the nitrile C, which issubsequently converted to acid E (e.g., NaOH, 1,3-propanediol). Thedibromoalkane can optionally be substituted to afford a substitutedcycloalkane analog of the invention. The integer n may be selected from0 to 2, resulting in cyclopentyl, cyclohexyl and cycloheptylintermediates, respectively. Alternatively, substituted or unsubstituted1,3-dibromopropane may be used to prepare a cyclobutyl analog of theinvention.

Coupling of acid E with either a primary amine (R⁴=H) or a secondaryamine is performed using peptide coupling reagents known in the artresulting in the corresponding amide (not shown). In an exemplaryembodiment the amide is formed using EDCI and HOBt in DMF as thecoupling reagents. In another exemplary embodiment, the amide is formedusing PyBOP in DMF as the coupling reagent. Exemplary couplingprocedures are described in General Procedures G to G3.

Referring to Scheme 1, the amide is then reduced using a reducing agent,such as borane. Exemplary borane reagents include BH₃.THF andborane•dimethylsulfide complexes. The resulting amine may be convertedto the corresponding salt form. For example, treatment of the amine withHCl in Et₂O affords the HCl salt, which may be recrystallized to givethe amine F as a solid.

Alternatively, the nitrile C can be reduced to the primary amine D usinga reducing agent, such as borane (e.g., BH₃.THF). The amine may beconverted to the corresponding salt form. For example, treatment of theamine with HCl in Et₂O affords the HCl salt, which may be recrystallizedto give a pure solid. The primary amine may be converted to a secondaryor tertiary amine by alkylation of the amino group as described below.

Alternatively, the carboxylic acid intermediate E can be activated byformation of an acid chloride, which may then be reacted with a primaryor secondary amine to give the amide, as outlined for an exemplarycyclopentylamine in Scheme 2, below.

In another approach, the nitrile C can be converted to the correspondingaldehyde G using a reducing agent, such as DIBAL (Scheme 3). Thealdehyde can then be converted to an amine, for example, throughreductive amination. This synthetic route is particularly useful for thepreparation of secondary amines of the invention (R⁴=H), as theamination of the aldehyde with a secondary amine to form a tertiaryamine may be sluggish.

3. Synthesis of Substituted Cyclopentyl Amines

Substituted cyclopentyl amines (n=0) can be synthesized according to theroute outlined in Scheme 4, below. The nitrile H may be synthesized fromdibromobutene and an appropriate aryl acetonitrile and can be convertedto the racemic cis and trans hydroxylamines I and J via reduction of thenitrile and hydroboration of the alkene with BH₃/H₂O₂, NaOH.Alternatively, reduction of H to the aldehyde K, followed by reductiveamination affords the ene-amine L. The double bond of L may be used tointroduce a substituent (X) into the 5-membered ring structure.

4. Synthesis of Secondary and Tertiary Amines

The synthesis of secondary amines from primary amines can, for example,be accomplished using the method described by De Luca et al., Synlett2004, 2570, which is incorporated herein by reference. The method isoutlined in Scheme 5, below. The primary amine is converted to theN-formylated intermediate M, which may be reduced to the correspondingmethyl amine. Typically, N-formylation followed by borane reduction ledto clean mono-methylated products.

Dialkylamine analogs of the invention can be synthesized according toScheme 6 below. In this method, a secondary amine is reacted withformaldehyde and concentrated formic acid to form a methylated tertiaryamine.

In an exemplary embodiment, reaction of a methyl amine analog (R³=Me)with a 1:1 mixture of concentrated formic acid and 37% aqueousformaldehyde at 100° C. for 1 h, typically gives the dimethyl amine ingood yield.

Another method useful for the synthesis of N,N-dimethyl and N-methylamines is shown in Scheme 7, below. Treatment of a primary amine withdiisopropylethylamine (DIEA) and methyl iodide (e.g., in CH₂Cl₂) leadsto the formation of both the N-methyl amine and the N,N-dimethyl amine,which can be separated chromatographically. Selectivity for either themono- or dimethylated product can be controlled by altering the ratio ofmethyl iodide to the amine as well as the reaction time. For example,mono-methylated analogs may be obtained selectively by keeping theconcentration of methyl iodide low and reaction times short.

5. Synthesis of 2-Substituted Cycloalkylamines

In an exemplary embodiment, cycloalkylamines of the invention aresubstituted at the 2-position. Such compounds may be synthesizedaccording to Scheme 8, below.

The method, outlined above for an exemplary 3,4-diphenyl cyclohexylamineof the invention, is applicable to the synthesis of 2-substitutedcycloalkylamines. Reaction of ethyl 2-oxocyclohexanecarboxylate N withan aryl-lead triacetate (e.g., 3,4-dichlorophenyllead triacetate)affords the ethyl 1-aryl)-2-oxocyclohexanecarboxylate O. NaBH₄ mediatedreduction of the keto-ester yields the alcohol P, which is subsequentlysaponified to afford the acid Q as a mixture of diastereomers. Amidecoupling and reduction of the resulting amide group affords the amine S.Chiral HPLC can be used to separate enantiomers/diastereomers. Thehydroxyl group of S may be functionalized (e.g., alkylation) or replacedby another substituent (X), such as a halogen atom (e.g., Cl or F) toyield compound T. Alternatively the hydroxyl group may be converted to aleaving group, which can subsequently be replaced with a selectednucleophile.

Corresponding dialkylamines of S or another hydroxyamine can be preparedfrom the corresponding primary amine or mono-alkylated analog (R⁴=H)when using an appropriate base, such as DIEA. For example, synthesis ofthe N,N-dimethyl amino-alcohols is prepared via alkylation of theN-methyl amines with methyl iodide and DIEA in acetone, as shown inScheme 9, below.

In another exemplary embodiment, the invention provides compounds, whichinclude a substituted alkyl-substituent within in the cycloalkyl ringstructure. For example, hydroxymethyl analogs may be synthesizedaccording to Scheme 10 below. The hydroxyl group may optionally bereplaced with another substituent, such as a halogen atom.

Referring to Scheme 10, the cycloalkyl lactone U is converted to thearyl derivative V. The lactone is then reacted with a lithium salt of aselected amine (e.g., dimethylamine) to give the amido-alcohol W, whichis subsequently reduced to the amine. For certain amides W (e.g.,dichlorophenyl analogs) it may be preferable to use LAH as the reducingagent instead of borane.

6. Synthesis of 3-Substituted Cycloalkylamines

In another exemplary embodiment, the compounds of the invention aresubstituted at the 3-position of the cycloalkyl ring. Exemplarysynthetic approaches for the preparation of such compounds are outlinedbelow. Referring to Scheme 11, treatment of ketone X with an arylGrignard reagent, followed by acidic hydrolysis and Michael addition ofthe cyanide (e.g., following the procedure described by Callis et al.,J. Org. Chem. 1996, 61, 4634) gives the cyano-ketone Y. Addition of analkyl lithium reagent to the carbonyl group affords the alcohol Z. Inone example, this addition is stereoselective and racemic cis Z isformed selectively. The cyano group of the alcohol Z can be reduced witha reducing agent, such as borane, and the resulting amine can be N—BOCprotected to give the racemic alcohol AA. Chiral chromatography followedby removal of the BOC group (e.g., by TFA) gives the enantiomeric cisamino-alcohols BB and CC. The amines can then be converted to thecorresponding alkyl amines (e.g., N-Me and NMe₂ derivatives) asdescribed herein, above.

Alternatively, the ketone Y can be treated with sodium borohydride toafford DD as a mixture of cis- and trans-diastereomers (Scheme 12). Inan exemplary embodiment, in which Ar is 3,4-dichlorophenyl, thecis-diastereomer of DD was formed primarily. Reduction of the nitrileand BOC protection of the resulting amino group affords the amine EE.The stereoisomers may be separated by chiral chromatography to give twopairs of enantiomers derived from cis EE and trans EE.

In addition, the hydroxyl group of any of the above analogs (e.g.,compound DD) can be functionalized or replaced to generate further3-substituted cyclohexyl amine analogs. For example, alkyation of thehydroxyl group of DD with methyl iodide gave the methoxy nitrile FF asdescribed in Scheme 13, below. Stereoisomers of FF may be isolatedthrough chiral chromatography. The nitrile is further processed togenerate an amine. For example, the nitrile group is reduced (e.g.,borane reduction) to afford the corresponding amine, which may then beconverted to the corresponding alkylamine (e.g., methylamine ordimethylamine) as described above.

In another exemplary embodiment, 3,3-difunctionalized cycloalkylaminederivatives are synthesized from the ketonitrile Y according to theprocedure outlined in Scheme 14, below. For example, the3,3-difluoro-cyclohexylamine GG is synthesized by treatment of theketonitrile Y with diethylaminosulfur trifluoride (DAST), followed byreduction of the nitrile group. Treatment of GG with methyl iodide andHunig's base leads to a separable mixture of the corresponding N-methylamine HH and N,N-dimethyl amine II. The enantiomers of both HH and IIcan be resolved by chiral chromatography.

7. Synthesis of 4-Substituted Cycloalkylamines

The invention further provides cycloalkylamines, in which the 4-positionof the cycloalkyl ring is derivatized. An exemplary method for thesynthesis of 4-substituted cycloalkyl amines was adapted from aprocedure described in WO 03/063797, which is incorporated herein byreference in its entirety for all purposes. The method is outlined inScheme 15, below.

Referring to Scheme 15, above, the acetonitrile JJ is condensed withmethyl acrylate to give the di-ester KK, which is cyclized via Dieckmanncondensation to give the cyclic hydroxy ester LL. Conversion of LL tothe key intermediate MM can, for example, be affected by heating thecompound in the microwave to about 160° C. Addition of an alkylnucleophile (such as MeLi or EtLi) gives a mixture of thehydroxynitriles cis NN and trans NN, which may be separated by silicagel column chromatography. In an exemplary embodiment, in whichAr=3,4-dichlorophenyl and in which propylmagnesium chloride is used asthe nucleophile, only the cis analog NN was obtained. Reduction of thenitrile group (e.g., borane) affords the corresponding amines cis 00 andtrans 00. Subsequent alkylation of the amines as described herein givecorresponding alkyl amines, such as methyl- and dimethyl amines.

Alternatively, the intermediate nitrile alcohol NN can be reacted withan alkyl lithium reagent (such as MeLi/NaBH₄) to add an R¹ group (e.g.,a methyl group) before further processing as shown in Scheme 16, below,to afford the racemic amine PP. The enantiomers of PP can be separatedby chiral chromatography.

In another exemplary embodiment, the ketonitrile MM is converted tochiral 4-hydroxy cyclohexylamines as shown in Scheme 17, below.Reduction of the carbonyl group (e.g., NaBH₄), followed by reduction ofthe nitrile group (e.g., borane) affords the primary amine QQ, whichtypically has cis configuration. Alternatively, the keto group of theketonitrile MM is reduced (e.g., NaBH₄) and the stereocenter carryingthe resulting hydroxyl group is inverted under Mitsonobu conditions toafford the hydroxynitrile RR, which is further processed to thecorresponding primary amine SS or to the respective alkyl amine asdescribed herein, above.

In an exemplary embodiment, the hydroxyl group of the intermediatehydroxynitrile RR is replaced or functionalized before furtherprocessing to the amine. For example, synthesis of O-alkylated orO-arylated species is accomplished through alkylation of thehydroxynitrile as shown in Scheme 18, below. Alkylation with methyliodide followed by borane reduction of the nitrile provides the primaryamine TT. A Mitsonobu protocol utilizing an alcohol, such as phenol,followed by borane reduction can be used to convert RR to thetrans-analog UU, with inverted stereochemistry at the 4-position.

In another exemplary embodiment, the intermediate hydroxyl nitrile RRcan be monofluorinated, for example, with morpholino sulfurtrifluorideor DAST to give the 4-fluoro species VV, which may be obtained alongwith the elimination product WW (Scheme 19), which can be separatedchromatographically. Both, the 4-fluoro nitrile VV and the alkene WW canbe converted to the corresponding primary amines or alkyl amine speciesas described herein, above. The double bond can optionally be used tointroduce a substituent in to the cycloalkyl ring (e.g, byhydroboration).

In yet another exemplary embodiment, the ketonitrile MM is converted toa 4,4-disubstituted cycloalkylamine. For example, synthesis of the4,4-difluoro amine XX could be affected via the action of morpholinosulfurtrifluoride or diethylamino trifluoride (DAST), followed byreduction of the nitrile group (e.g., by borane) as outlined in Scheme19, below. The resulting primary amine may be converted to thecorresponding alkyl amines as described herein.

The 4-position of the present cycloalkylamines can also be derivatizedvia the formation of an intermediate epoxide, as shown in Scheme 21,below. For example, epoxidation of the ketonitrile MM usingtrimethylsulfonium iodide/KO^(t)Bu affords diastereomeric epoxides,which may be separated by column chromatography. The epoxide ring can beopened in a regioselective reaction with an appropriate nucleophile,such as TBAF/HF to give the corresponding hydroxyl derivative andsubsequent reduction of the nitrile group affords the primary amine,such as the fluoromethyl analog YY. The primary amine is optionallyconverted to corresponding alkylamine species as described herein.

In another embodiment, the invention provides cycloalkylamines with anadditional amino group substituent in the cycloalkyl ring structure. Inone example, the amine substituent is located at the 4-position of thecycloalkyl ring. For instance, the ketonitrile MM can be converted to a4-amino-cyclohexylamine using the exemplary synthetic conversionsoutlined in Scheme 22, below. Protection of the keto group of MM (e.g.,through formation of a dioxolane), reduction of the nitrile group (e.g.,with borane), alkylation of the primary amine (e.g., methylation withmethyl iodide) and deprotection of the ketone functionality affords theanalog ZZ. Reductive amination of the keto group (e.g., using methylamine and sodium cyanoborohydride) affords a mixture of diastereomers,which may be separated by preparative HPLC to give the correspondinganalogs cis- and trans AAA.

8. Introduction of R¹ and/or R²

The invention further provides cycloalkylamines, in which theamine-bearing side chain is substituted with substituents R¹ and R². Inan exemplary embodiment, R¹ is a short alkyl group, such as C₁- toC₄-alkyl. Introduction of a R¹ group can, for example, be accomplishedusing the synthetic procedure outlined in Scheme 23, below.

For example, addition of an alkyl lithium reagent to the aryl nitrile C,followed by reduction of the resulting imine affords the racemic primaryamines BBB. The corresponding enantiomeric primary amines may beobtained by chiral HPLC chromatography.

9. Synthesis of Cycloalkylamines, in which R¹ and R³ are Joined in aRing

The invention further provides cycloalkylamines, in which the aminenitrogen is part of a ring. In an exemplary embodiment, R¹ and R³,together with the atoms to which they are attached, are joined to form a3- to 7-membered ring, such as a substituted or unsubstitutedpyrrolidine or piperidine ring. An exemplary synthetic method for thepreparation of pyrrolidine analogs according to this embodiment isoutlined in Scheme 24, below.

For example, addition of an acetal Grignard reagent to an aryl (e.g.3,4-dichlorophenyl or 2-naphthyl) (R)-sulfinamine leads to thecorresponding sulfinamide CCC as mixtures of diastereomers. Subsequenthydrolysis (e.g., 6M HCl in acetone) can be used to remove both, thesulfinamine auxiliary and ketal side chain. Intramolecular reductiveamination (e.g., using polymer bound sodium cyanoborohydride) affordsthe racemic pyrollidine DDD.

D. Pharmaceutical Compositions

In a second aspect, the invention provides a pharmaceutical compositionincluding a compound of the invention (e.g., a compound of Formulae (I)to (IV)) or a pharmaceutically acceptable salt or solvate thereof, andat least one pharmaceutically acceptable carrier.

As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for oral administration,e.g., tablets, drenches (aqueous or non-aqueous solutions orsuspensions), parenteral administration (including intravenous andintramuscular), or epidural injection as, for example, a sterilesolution or suspension, or sustained release formulation. Thepharmaceutical compositions of the present invention may also bespecifically formulated for administration transdermally.

The pharmaceutical compositions of the invention may be administeredorally, parenterally, subcutaneously, transdermally, nasally, or by analsuppository. The pharmaceutical compositions of the invention may alsobe administered using controlled delivery devices.

Formulations of the present invention include those suitable for oraland parenteral administration, particularly intramuscular, intravenousand subcutaneous administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated and the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect,without being toxic to the patient. Generally, out of one hundredpercent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,liposomes, micelle forming agents, e.g., bile acids, and polymericcarriers, e.g., polyesters and polyanhydrides; and a compound of thepresent invention. In certain embodiments, an aforementioned formulationrenders orally bioavailable a compound of the present invention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, caplets, lozenges (usinga flavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia), each containing a predeterminedamount of a compound of the present invention as an active ingredient. Acompound of the present invention may also be administered as a bolus,electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, caplets, pills, dragees, powders, granules and thelike), the active ingredient is mixed with one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol, glycerolmonostearate, and non-ionic surfactants; (8) absorbents, such as kaolinand bentonite clay; (9) lubricants, such a talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-shelled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue. Pharmaceuticalcompositions or unit dosage forms of the present invention in the formof prolonged-action tablets may comprise compressed tablets formulatedto release the drug substance in a manner to provide medication over aperiod of time. There are a number of tablet types that includedelayed-action tablets in which the release of the drug substance isprevented for an interval of time after administration or until certainphysiological conditions exist. Repeat action tablets may be formed thatperiodically release a complete dose of the drug substance to thegastrointestinal fluids. Also, extended release tablets thatcontinuously release increments of the contained drug substance to thegastrointestinal fluids may be formed.

Compounds of the invention can be also administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the compounds of this invention. The invention thus encompassessingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, temperature, enzymes, water, or other physiological conditions orcompounds.

Compounds of the present invention may also be formulated astransdermal, topical, and mucosal dosage forms, which forms include, butare not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue.

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The preparations of the present invention may be given orally andparenterally. They are of course given in forms suitable for eachadministration route. For example, they are administered in tablets orcapsule form, by injection, and by intravenous administration. In oneembodiment, oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.005 mg per kilogram toabout 5 mg per kilogram of body weight per day.

The terms “treatment” or “treating” is intended to encompass therapy,preventing (prophylaxis), preventing relapse, and amelioration of acutesymptoms. Note that “treating” refers to either or both of theamelioration of symptoms and the resolution of the underlying condition.In many of the conditions of the invention, the administration of acompound or composition of the invention may act not directly on thedisease state, but rather on some pernicious symptom, and theimprovement of that symptom leads to a general and desirableamelioration of the disease state.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep, as well as poultry and pets in general.

The compounds and pharmaceutical compositions of the invention can beadministered in conjunction with other pharmaceutical agents, forinstance antimicrobial agents, such as penicillins, cephalosporins,aminoglycosides and glycopeptides. Conjunctive therapy thus includessequential, simultaneous and separate administration of the activecompound in a way that the therapeutic effects of the first administeredagent have not entirely disappeared when the subsequent agent isadministered.

IV. Methods A. Binding to Monoamine Transporter

In another aspect the invention provides a method of binding a compoundof the invention to a monoamine transporter. The method includescontacting the monoamine transporter and a compound of the invention.

In yet another aspect, the invention provides a method of inhibitingbinding of a monoamine transporter ligand to a monoamine transporter(such as serotonin transporter, dopamine transporter and norepinephrinetransporter). The method includes contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment themonoamine transporter ligand is an endogenous monoamine, such asserotonin, dopamine or norepinephrine. In another exemplary embodiment,the ligand is a drug molecule or another small molecule known to havebinding affinity to a monoamine transporter. In another exemplaryembodiment, the monoamine transporter ligand is a radioactively labeledcompound, known to bind to the monoamine transporter.

In an exemplary embodiment, inhibition of ligand binding is shown usingan ex vivo binding assay, such as those described herein, below inExample 7. In an exemplary embodiment, the compound of the inventioninhibits mean binding by between about 1% and about 100%, preferably bybetween about 10% and about 100%, more preferably by between about 20%and about 90% when compared to vehicle. Inhibition of mean binding ispreferably dose dependent.

B. Inhibition of Monoamine Transporter Activity

In yet another aspect, the invention provides a method of modulating(e.g, inhibiting, augmenting) the activity of at least one monoaminetransporter, such as serotonin transporter, dopamine transporter andnorepinephrine transporter. The method includes contacting the monoaminetransporter and a compound of the invention. In an exemplary embodiment,the monoamine transporter is contacted with a compound of the inventionby administering to a subject a therapeutically effective amount of thecompound of the invention, e.g., a compound according to Formulae (I) to(V), or a pharmaceutically acceptable salt or solvate thereof. In apreferred embodiment, the subject is a human. In another exemplaryembodiment, the monoamine transporter is dopamine transporter (DAT),serotonin transporter (SERT) or norepinephrine transporter (NET). Inanother exemplary embodiment, the compound of the invention inhibits theactivity of at least two different monoamine transporters. Inhibition ofmonoamine transporter activity may be measured using assays known in theart. Exemplary assay formats include in vitro functional uptake assays(Example 6). In an exemplary embodiment, the functional uptake assayutilizes an appropriate cell-line expressing a desired monoaminetransporter. In another exemplary embodiment, the functional uptakeassay utilizes synaptosomes isolated from brain tissue of an appropriateorganism. Alternatively, inhibition of monoamine transporter activitymay be assessed using receptor binding experiments known in the art,e.g., utilizing appropriate membrane preparations. Another assayinvolves treatment of a test subject (e.g., a rat) with a compound ofthe invention as well as a reference compound, followed by isolation ofbrain tissue and ex vivo analysis of receptor occupancy, as describedherein.

C. Inhibition of Monoamine Uptake

In yet another aspect, the invention provides a method of inhibitinguptake of at least one monoamine (e.g., dopamine, serotonin,norepinephrine) by a cell. The method includes contacting the cell witha compound of the invention. In an exemplary embodiment, the cell is abrain cell, such as a neuron or a glial cell. In one example, inhibitionof monoamine uptake occurs in vivo. In an organism, neuronal uptake(also termed reuptake) of a monoamine such as dopamine or serotoninoccurs, for example, from the synaptic cleft. Thus, in one embodiment,the neuronal cell is in contact with a synaptic cleft of a mammal. Inanother exemplary embodiment, inhibition of monoamine uptake occurs invitro. In those methods the cell, may be a brain cell, such as aneuronal cell or a cell-type, which expresses a recombinant monoaminetransporter.

In one embodiment, the compound inhibits uptake of at least twodifferent monoamines. This can, for example, be shown by performingvarious in vitro functional uptake assays utilizing a cell-type, whichsimultaneously expresses multiple different monoamine transporters (suchas isolated synaptosomes), or may be shown by using two different celltypes, each expressing a different monoamine transporter, such as arecombinant dopamine transporter, together with an appropriate, labelledmonoamine (Example 6) Inhibition of monoamine uptake is demonstratedwhen the inhibitor (e.g., a compound of the invention) has an IC₅₀ ofbetween about 0.1 nM and about 10 μM, preferably between about 1 nM andabout 1 μM, more preferably between about 1 nM and about 500 nM, andeven more preferably between about 1 nM and about 100 nM in a functionalmonoamine uptake assay, such as those described herein below.

D. Treatment of CNS Disorders

In another aspect, the invention provides a method of treatingdepression by inhibiting the activity at least one monoaminetransporter. The method includes administering to a mammalian subject acompound of the invention. In an exemplary embodiment, the mammaliansubject is a human. In another exemplary embodiment, the compound of theinvention inhibits the activity of at least two different monoaminetransporters. For example, the compound of the invention inhibits theactivity of at least two of serotonin transporter, dopamine transporterand norepinephrine transporter. Inhibition of monoamine transporteractivity may be shown by functional monoamine uptake assays as describedherein below (Example 6). Demonstration of anti-depressant activity of acompound of the invention may be shown by utilizing an appropriateanimal model of depression, such as the Rat Forced Swim Test, the MouseTail Suspension Test and Rat Locomotor Activity Analyses (Example 8).The Rat Forced Swim Test is also suitable for the analysis of compoundshaving activities against more than one monoamine transporter (mixedmonoamine transporter activity). For example, an increase in swimmingactivity is indicative of serotonin reuptake inhibition, while anincrease in climbing activity is indicative of norepinephrine reuptakeinhibition. In a preferred embodiment, the compounds of the inventionare active in at least one animal model, which can be used to measureanti-depressant-like activities, for instance those assessingimmobility. In an exemplary embodiment, the compounds of the inventionare active when they inhibit mean immobility by between about 5% andabout 90%, preferably between about 10% and about 70% and morepreferably between about 10% and about 50% in at least one animal model,when compared to vehicle.

In yet another aspect, the invention provides a method of effecting ananti-depressant-like effect. The method includes administering to amammalian subject in need thereof a therapeutically effective amount ofa compound or composition of the invention, e.g., a compound accordingto Formulae (I) to (IV), or a pharmaceutically acceptable salt orsolvate thereof. Anti-depressant-like effects may be measured using ananimal model of disease, such as those described herein.

In a further aspect, the invention provides a method of treating acentral nervous system disorder. The method includes administering to asubject in need thereof a therapeutically effective amount of acomposition or compound of the invention, e.g., a compound according toFormulae (I) to (IV), or a pharmaceutically acceptable salt or solvatethereof. In a preferred embodiment, the subject is a human.

In another exemplary embodiment, the central nervous system disorder isa member selected from the group consisting of depression (e.g., majordepressive disorder, bipolar disorder, unipolar disorder, dysthymia andseasonal affective disorder), cognitive deficits, fibromyalgia, pain(e.g., neuropathic pain), sleep related disorders (e.g., sleep apnea,insomnia, narcolepsy, cataplexy) including those sleep disorders, whichare produced by psychiatric conditions, chronic fatigue syndrome,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxieties (e.g.general anxiety disorder, social anxiety discorder, panic disorder),obsessive compulsive disorder, posttraumatic stress disorder, seasonalaffective disorder (SAD), premenstrual dysphoria, post-menopausalvasomotor symptoms (e.g., hot flashes, night sweats), andneurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease and amyotrophic lateral sclerosis), manic conditions, dysthymicdisorder, and cyclothymic disorder. In a preferred embodiment, the CNSdisorder is depression, such as major depressive disorder. In anexemplary embodiment, the compounds of the invention are useful to treattwo conditions/disorders, which are comorbid, such as cognitive deficitand depression.

Central nervous system disorder includes cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorders, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes without limitation post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated using themethods of the invention include obesity; migraine or migraine headache;urinary incontinence, including without limitation involuntary voidingof urine, dribbling or leakage of urine, stress urinary incontinence(SUI), urge incontinence, urinary exertional incontinence, reflexincontinence, passive incontinence, and overflow incontinence; as wellas sexual dysfunction, in men or women, including without limitationsexual dysfunction caused by psychological and/or physiological factors,erectile dysfunction, premature ejaculation, vaginal dryness, lack ofsexual excitement, inability to obtain orgasm, and psycho-sexualdysfunction, including without limitation, inhibited sexual desire,inhibited sexual excitement, inhibited female orgasm, inhibited maleorgasm, functional dyspareunia, functional vaginismus, and atypicalpsychosexual dysfunction.

EXAMPLES 1. General Procedures

In the examples, below, the following general experimental procedureswere used unless otherwise noted: All commercial reagents were usedwithout further purification. Anhydrous reactions were performed inflame-dried glassware under N₂. NMR spectra were recorded on a Varian400 MHz spectrometer in deuterochloroform or methanol-d⁴ withtrimethylsilane (TMS) as an internal reference. Silica gel columnchromatography was performed using an ISCO Combiflash system withdetection at 254 nm or using ISCO normal phase silica gel cartridges.

Analytical HPLC

Analytical HPLC was performed on a Hewlett Packard Series 1100 pumpconnected to an Agilent Zorbax RX-C18 5 μm, 4.6×250 mm column, withdetection on a Hewlett Packard Series 1100 UV/Vis detector monitoring at214 and 254 nm. Typical flow rate=1 ml/min. Three different HPLC columnsand various elution protocols were used. For example, (1) Agilent ZorbaxRX-C18 5 μm, 4.6×250 mm column running a linear gradient. Solvent A=H₂Ow/0.05% TFA, Solvent B=MeCN w/0.05% TFA. Time 0 min=5% Solvent B, time 4min=40% Solvent B, time 8 min=100% Solvent B, 12 min=5% Solvent B, 20min=5% Solvent B; (2) Phenomenex 3μ C18 column running a 3 minutegradient of 5→100% B (acetonitrile/0.1% formic acid) and solvent A(water/0.1% formic acid); (3) Phenomenex 5μ C18 column running a 5minute gradient of 5→100% B where solvent B (acetonitrile/0.1% formicacid) and solvent A (water/0.1% formic acid).

Reverse Phase HPLC Purification

Reverse phase HPLC purification was performed on a Gilson system using aPhenomenex 5μ C18 (50×21.2 mm) column. The standard separation methodwas: 10 minute gradient of 10→100% B (acetonitrile/0.1% formic acid) insolvent A (water/0.1% formic acid). Crude samples were typicallydissolved in MeOH. Fractions were concentrated by Genovac(centrifugation at low pressure).

GC-MS

Gas chromatography was performed on a Hewlett Packard 6890 Series GCSystem with an HP1 column (30 meters, 0.15μ film thickness) coupled to aHewlett Packard 5973 Series Mass Selective Detector. The followinglinear temperature gradient was used: 100° C. for 5 minutes, then 20°C./min to 320° C. Hold @ 320° C. for 10 minutes.

LCMS

LCMS was performed on an Agilent 1100 Series system connected to aMicromass Platform LC. The following column and gradient was used:Column: Luna C18(2), 3 um particle size 30×2.0 mm column dimension. Flowrate=0.5 mL/min, Solvent A=0.1 M NH₄Ac in 95% H₂O, 5% MeOH, pH 6.0,Solvent B=Solvent B: 0.1 M NH₄Ac in MeOH. Linear gradient with 6entries: Time 0 min=100% Solvent A, time 10 min=100% Solvent B, time 12min=100% Solvent B, time 12 min 10 sec=100% Solvent A, time 14 min=100%Solvent A, time 14 min 20 sec=100% Solvent A.

Microwave (μW) Recrystallization

The crude salt (e.g., HCl salt) was loaded into a microwave vessel witha stir bar. The recrystallization solvent was added and the vessel washeated at the target temperature for a given time. The vessel was cooledto 50° C. in the reactor, was then removed and allowed to slowly cool toRT. N,N-dimethyl amines were typically recrystallized in EtOAc orEtOAc:CH₃CN (2:1). N-Me or primary amines were typically recrystallizedin CH₃CN.

Formylation-Reduction 1 (General Procedure A)

The amine free base was dissolved in CH₂Cl₂ at approximately 0.4 M andconcentrated formic acid (1.0 eq relative to the amine),1-chloro-3,5-dimethoxytriazine (1.1 eq), DMAP (0.03 eq) andN-methylmorpholine (1.1 eq) were added in this order. The solution washeated in the μW (60° C., 10 min.) and cooled to RT. The reaction wasmonitored by HPLC. When the starting material was consumed, the crudereaction mixture was diluted with CH₂Cl₂ (15 mL) and washed with aqueousHCl (twice), saturated aqueous K₂CO₃ and brine. The crude product wasdried (Na₂SO₄), filtered and concentrated. The crude N-formyl amide wasdissolved in anhydrous THF at approximately 0.2 M and borane-THF (e.g.,1.0 M in THF, 3 eq) was added dropwise. The clear solution was heatedvia μW (150° C., 30 min, FHT), cooled to RT and quenched with 6M HCl(e.g., 10 mL). The solution was washed twice with Et₂O (e.g., 20 mL).The aqueous phase was adjusted to pH 12 with 3M NaOH and was then washedthree times with EtOAc (e.g., 20 mL). The combined organic layers weredried (Na₂SO₄), filtered and concentrated.

Formylation-Reduction 2 (General Procedure B)

To acetic anhydride (1 eq relative to the amine) under nitrogen at 0° C.was added formic acid (3 eq) dropwise over 3 min. After stirring thereaction mixture for 1 h, a 0.1 M solution of the amine (1 eq) in THFwas added dropwise over 5 min. The mixture was allowed to slowly warm,stirring at room temperature for 3 d. The volatiles were removed invacuo and the residue was purified over silica gel. To a solution of theformamide (1 eq) in THF (10 mL) under nitrogen was added BH₃.S(CH₃)₂ (2M in THF, 2 eq) dropwise over 5 min. The mixture was stirred at roomtemperature for 20 hours. MeOH, and 2 N aqueous HCl were added and themixture was washed with diethyl ether (50 mL). The pH was adjusted to 14by addition of 2 N NaOH and the mixture was extracted with diethyl ether(50 mL). The combined organic phases were dried (sodium sulfate),filtered, and concentrated. The crude N-methyl amine was purified byeither Gilson RP-HPLC or by transformation to the HCl salt andrecrystallization in the indicated solvent.

HCl Salt Formation

The crude amine was dissolved in Et₂O (e.g., 3 mL) and HCl (e.g., 3-5mL, 2.0 M in Et₂O). The solution was stirred for 1 h and evaporatedtwice from CH₂Cl₂ (e.g., 20 mL). The crude HCl salt was recrystallizedin the indicated solvent, filtered and dried in vacuo.

Eschweiler-Clarke N,N-Dimethylation (General Procedure C)

The amine free base (up to 100 mg) was suspended in 37% aqueousformaldehyde (3 mL) and concentrated formic acid (3 mL) was added. Theyellowish solution was heated at 100° C. for 1 h and cooled to RT. Theclear solution was poured into saturated aqueous K₂CO₃ (20 mL) andwashed with EtOAc (3×20 mL). The organic washes were combined, washedwith brine (1×10 mL), dried (Na₂SO₄), filtered and concentrated. Thecrude amine was dissolved in Et₂O (3 mL) and HCl (3-5 mL, 2.0 M in Et₂O)was added. The solution was stirred for 1 h and concentrated with CH₂Cl₂(2×20 mL). The crude HCl salt was recrystallized in the indicatedsolvent, filtered and dried in vacuo. Alternatively, the dimethylaminecould be purified on the reverse-phase HPLC system if recrystallizationwas not unsuccessful.

Methylation Via Reductive Amination with Formaldehyde and NaB(CN)H₃(General Procedure D)

To a stirred solution of the amine (approximately 0.05 M, 1 eq), 37%formaldehyde (10 eq), and acetic acid (1 drop) in CH₂Cl₂ at roomtemperature was added NaBH(OAc)₃ (4 eq). The reaction mixture wasstirred for 3 days. Saturated NaHCO₃ solution was then added and themixture was extracted with EtOAc. The combined organic layers were dried(sodium sulfate), filtered, and concentrated. The crude amine waspurified by either Gilson RP-HPLC or by transformation to the HCl saltand recrystallization.

Borane Reduction of Amide or Nitrile (General Procedure E)

To a solution of the nitrile in anhydrous THF (final concentration:about 0.1M to about 0.2 M) was added dropwise borane-THF (e.g., 1.0M inTHF, 3 eq). The reaction mixture was heated in the microwave (maximumtemperature: 150° C., about 1 min to about 40 min), cooled to roomtemperature and then quenched with 6N HCl. The solution was washed withEtOAc. The aqueous phase was adjusted to pH 12 with 3N NaOH andextracted three times with EtOAc. The combined organic layers were dried(Na₂SO₄), filtered and concentrated.

The crude amine was purified by column chromatography and/or isolated asthe HCl salt after precipitation from ether (e.g., Et₂O) and HCl (e.g.,2.0 M in Et₂O). The crude HCl salt was optionally recrystallized fromthe indicated solvent.

Reduction of Nitrile with LiAlH₄ (General Procedure E1)

To a 0.05 M solution of the nitrile (1 eq) in diethyl ether was addedLiAlH₄ (5 eq). The reaction mixture was heated at reflux for 30 minbefore NaOH solution was slowly added to quench the reaction. Theproduct was extracted with diethyl ether. The combined extracts weredried (Na₂SO₄), filtered and concentrated. The residue was dissolved inMeOH and purified by reverse phase HPLC.

JianguoMa Alkylation (General Procedure F)

The primary amine free base or HCl salt was dissolved/suspended inanhydrous CH₂Cl₂ (volume to make amine concentration=0.1 M) and neatanhydrous diisopropylethylamine (3 eq) and methyl iodide (1-5 equiv.depending on desired outcome) was added. The clear solution was stirredat RT for 1-5 h and monitored by HPLC. Longer reaction times favor theformation of the N,N-dimethyl amines; shorter reaction times favorformation of the N-methyl amines. The reaction was checked by HPLC andquenched with MeOH (5 mL) when the desired ratio ofN-methyl:N,N-dimethyl amines was reached. The reaction was concentratedunder reduced pressure and loaded directly onto a Biotage samplet.Purification by silica gel column chromatography used hexane/0.1% DEA asthe non-polar phase and ethyl acetate as the polar phase. The followinggradient was employed: equilibration with hexane/0.1% DEA, 3 columnvolumes (CV), linear 0-50% ethyl acetate over 7 CV, hold at 50% ethylacetate for 5.5 CV. Fractions were checked by HPLC and LCMS. Productfractions eluted around fractions 7-15. Positive fractions wereconcentrated and converted into HCl salts.

Amide Coupling (General Procedure G)

A solution of the respective carboxylic acid (approximately 0.1M, 1 eq),the respective amine (1-2 eq), N-methylmorpholine (1-2 eq) and PyBOP(1-2 eq) in anhydrous DMF was stirred at RT overnight (The reactionmixture may optionally include DMAP). The reaction mixture was pouredinto H₂O (e.g., 20 mL) and washed three times with Et₂O (e.g., 3×20 mL).The combined organic layers were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by either silica gel columnchromatography, reverse phase HPLC or by transformation to the HCl saltand recrystallization.

Alkyl Lithium Addition to Nitrile (General Procedure I)

To a solution of arylcyclohexanecarbonitrile (approximately 0.16 M,e.g., 12.8 g, 49.0 mmol) in anhydrous toluene at 0° C. was addeddropwise a solution of methyllithium (1.6 M, 1.5 eq) over 10 min. Theice bath was removed and the reaction mixture stirred for 30 min.Methanol (65 eq) and sodium borohydride (6 eq) were added portionwise.The mixture was stirred for 45 min and was then carefully quenched with6 N HCl. The mixture was washed with ethyl acetate. The pH of theaqueous layer was adjusted to 14 by addition of 6 N NaOH and was thenextracted with ethyl acetate. The combined organic layers were dried(Na₂SO₄), filtered and concentrated to give the crude racemic primaryamine. The crude amine was purified by either Gilson RP-HPLC or bytransformation to the HCl salt and recrystallization.

Cycloalkyl Nitrile Synthesis (General Procedure J)

To a 0.1 M suspension of sodium hydride (2.5 eq) in anhydrous DMSO wasadded a 0.4 M solution of aryl acetonitrile (1 eq) in anhydrous DMSOdropwise over 35 min. The mixture was stirred for 30 min and was thenadded to a 0.24 M solution of 1,5-dibromopentane (1.5 eq) in anhydrousDMSO dropwise over 20 min. The mixture was stirred overnight at roomtemperature, poured into water and extracted with chloroform or CH₂Cl₂.The organic layers were combined, washed with water, dried (Na₂SO₄),filtered and concentrated. The resulting residue was chromatographed onsilica gel to give the arylcyclohexanecarbonitrile.

Alkylation of Alcohol (General Procedure Y)

To a 0.2 M solution of the alcohol (1 eq) in THF was added NaH (60% inmineral oil, 1.5 eq). The reaction mixture was stirred for 20 min beforealkyl halide (2 eq) was added. The reaction mixture was stirred for 4 hand was then quenched with saturated NH₄Cl solution. The product wasextracted with diethyl ether. The combined organic layers were dried(Na₂SO₄), filtered and concentrated. The residue was purified by silicagel column chromatography (e.g., ethyl acetate/hexane) to giveO-alkylated product.

Lithio-Amine Addition to Lactone (General Procedure AA)

To a cold solution of alkylamine (5 eq) at −78° C. was added n-Buli (3eq) and the reaction mixture was stirred for five minutes. A 0.3 Msolution of the aryl lactone (1 eq) in anhydrous THF was then added. Themixture was stirred at the low temperature for one hour and at ambienttemperature for an additional hour. The reaction was then quenched withsaturated ammonium chloride and extracted with MTBE. The combinedorganic layers were evaporated and the crude oil purified on silica gelto give the amide.

Example 1 Synthesis of Cycloalkyl Amines 1.1. Synthesis of CycloalkylNitriles

The following exemplary cycloalkylcarbonitriles were prepared from therespective aryl nitriles according to General Procedure J:

1-(biphenyl-4-yl)cyclohexanecarbonitrile

HPLC R_(t)=11.29 min; GC-MS, SCOUT program 13.85 min, M⁺ 261.

1-(thiophen-2-yl)cyclohexanecarbonitrile

HPLC R_(t)=10.24 min; GC-MS, SCOUT program 8.42 min, M⁺ 191.

1-(naphthalen-1-yl)cyclohexanecarbonitrile

HPLC R_(t)=10.82 min; GC-MS 12.6 min, M⁺ 235.

1-(4-(trifluoromethoxy)phenyl)cyclohexanecarbonitrile

HPLC R_(t)=10.76 min; GC-MS 8.59 min, M⁺ 269.

1.2. Synthesis of Primary Amines from Cycloalkyl Nitriles

The primary amines summarized in Table 1, below, were prepared from thecorresponding nitriles according to the indicated General Procedures.Enantiomeric mixtures of selected primary amines were separated bychiral chromatography using the indicated chromatographic methods togive the fast moving enantiomer (E1) and the slow moving enantiomer(E2), respectively.

TABLE 1 Summary of Exemplary Primary Amines General Ar n R¹ Procedure(1-(3,4-dichlorophenyl)cyclobutyl)methanamine (1)

1 H E HPLC R_(t) = 8.16 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.48 (d, J = 8.31Hz, 1H), 7.37 (m, 1H), 7.14-7.10 (m, 1H), 3.23 (m, 2H), 2.44-2.34 (m,2H), 2.29-2.20 (m, 2H), 2.14-2.05 (m, 1H), 1.93-1.86 (m, 1H); LC-MS 6.91min, (M + 1)⁺ 230 @ 7.27 min. (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine (2)

3 CH₃ I Chiral HPLC (AD column; 98:2:0.1hexanes:isopropanol:diethylamine, 280 nm) to give 2 E1 (R_(t) = 8 min)and 2 E2 (R_(t) = 10 min). HPLC R_(t) = 8.77 min; ¹H NMR (400 mHz,CD₃OD) 7.52 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.26 (dd, J =2.2, 8.8 Hz, 1H), 3.21 (1H, under solvent peak), 2.35 (broad d, 13.2 Hz,1H), 2.24 (broad d, 13.9 Hz, 1H), 1.57-1.46 (m, 5H), 1.24-1.11 (m, 3H),1.04 (d, J = 6.6 Hz, 3H); LC-MS 8.13 min, (M + 1)⁺ 272 @ 8.37 min (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-methylbutan-1-amine (3)

3 iso- butyl I HPLC R_(t) = 9.49 min; ¹H NMR (400 MHz, MeOH-d⁴) 7.4-7.38(m, 2H), 7.17-7.15 (m, 1H), 2.58-2.55 (m, 1H), 2.27-2.18 (m, 2H),1.64-1.44 (m, 5H), 1.27-1.11 (m, 7H), 0.83 (d, J = 6.96, 3H), 0.78 (d, J= 6.96 Hz, 3H), 0.69-0.62 (m, 1H); LC-MS 9.81 min, (M + 1)⁺ 314 @ 9.95min. (1-(3,4-dichlorophenyl)cycloheptyl)methanamine (4) 4

4 H E HPLC R_(t) = 8.96 min; ¹H NMR (400 MHz, CDCl₃) 7.51-7.48 (m, 2H),7.29 (dd, J = 2.2, 8.4 Hz, 1H), 3.0 (s, 2H), 2.12-2.07 (m, 2H),1.79-1.73 (m, 2H), 1.66-1.38 (m, 7H); LC-MS 8.61 min, (M + 1)⁺ 272 @8.81 min (±) 1-(1-(4-methoxyphenyl)cyclohexyl)ethanamine (5)

3 CH₃ I HPLC R_(t) = 8.07 min; LC-MS 5.57 min, (M + 1)⁺ 234 @ 5.98 min.(±) 1-(1-(thiophen-2-yl)cyclohexyl)ethanamine (6)

3 CH₃ I HPLC R_(t) = 7.81 min; LC-MS 4.90 min, (M + 1)⁺ 210 @ 5.78 min.(±) 1-(1-(biphenyl-4-yl)cyclohexyl)ethanamine (7)

3 CH₃ I HPLC R_(t) = 9.07 min; LC-MS 7.47 min, (M + 1)⁺ 280 @ 7.94 min.(1-(biphenyl-4-yl)cyclohexyl)methanamine (8)

3 H E HPLC R_(t) = 8.96 min; ¹H NMR (400 MHz, CD₃OD) 7.64 (d, J = 8.43Hz, 2H), 7.57 (d, J = 7.70 Hz, 2H), 7.47 (d, J = 8.06 Hz, 2H), 7.39-7.36(m, 2H), 7.27 (t, J = 7.33 Hz, 1H), 3.01 (s, 2H), 2.26-2.24 (m, 2H),1.64-1.52 (m, 5H), 1.39-1.38 (m, 3H); LC-MS 7.48 min, (M + 1)⁺ 266 @7.86 min. (1-(thiophen-2-yl)cyclohexyl)methanamine (9)

3 H E HPLC R_(t) = 7.62 min; ¹H NMR (400 MHz, CD₃OD) 7.36 (dd, J = 1.1,4.76 Hz, 1H), 7.02-6.98 (m, 2H), 2.98 (s, 2H), 2.13-2.01 (m, 2H), 1.98-1.35 (m, 8H); LC-MS 4.55 min, (M + 1)⁺ 196 @ 5.12 min.(1-(4-methylthio)phenyl)cyclohexyl)methanamine (10)

3 H E HPLC R_(t) = 8.30 min; ¹H NMR (400 MHz, CD₃OD) 7.33-7.26 (m, 4H),2.96 (s, 2H), 2.42 (d, J = 1.47 Hz, 3H), 2.19-2.16 (m, 2H), 1.60-1.49(m, 5H), 1.39-1.31 (m, 3H); LC-MS 6.07 min, (M + 1)⁺ 236 @ 6.45 min. (±)1-(1-(4-chlorophenyl)cyclohexyl)ethanamine (11)

3 CH₃ I HPLC R_(t) = 8.38 min; LC-MS 6.13 min, (M + 1)⁺ 238 @ 5.84 min.(1-(naphthalen-1-yl)cyclohexyl)methanamine (12)

3 H E HPLC R_(t) = 8.49 min. ¹H NMR (400 MHz, CD₃OD) 8.39 (d, J = 8.43Hz, 1H), 7.90 (d, J = 7.70 Hz, 1H), 7.82 (d, J = 8.06 Hz, 1H), 7.58 (d,J = 7.33 Hz, 1H), 7.51-7.42 (m, 3H), 3.64 (bs, 2H), 2.56-2.51 (m, 2H),1.98-1.94 (m, 2H), 1.62-1.50 (m, 6H); LC-MS 7.40 min, (M + 1)⁺ 240 @7.62 min. (±) 1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (13)

3 CH₃ I SFC w/AD column and 33% MeOH/0.1% DEA, 25° C. column temp., 10ml/min total flow, 280 nm to give the fast moving enantiomer 13 E1(R_(t) = 3.8 min) and the slow moving enantiomer 13 E2 (R_(t) = 5 min).13 E1 LC-MS (M + 1)⁺ 254 @ 8.31 min 13 E2 LC-MS (M + 1)⁺ 254 @ 8.33 min(±) 1-(1-(4-chlorophenyl)cyclohexyl)-2-methylpropan-1-amine (14)

3 iso- propyl I HPLC R_(t) = 8.89 min; LC-MS 8.67 min, (M + 1)⁺ 266 @8.85 min. (1-(4-(trifluoromethoxy)phenyl)cyclohexyl)methanamine (15)

3 H E HPLC R_(t) = 8.63 min; ¹H NMR (400 MHz, CD₃OD) 7.50 (d, J = 9.16Hz, 2H), 7.28 (d, J = 8.80 Hz, 2H), 3.02 (s, 2H), 2.19 (d, J = 12.8 Hz,2H), 1.67-1.31 (m, 8H); LC-MS 7.93 min, (M + 1)⁺ 274 @ 8.18 min.1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (16)

3 CH₃ I SFC w/AS column and 30% MeOH/0.1% DEA, 280 nm. 16 E1: HPLC R_(t)= 2.23 min; LC-MS 7.56 min, (M + 1)⁺ 254 @ 7.78 min 16 E2: LC-MS 7.59min, (M + 1)⁺ 254 @ 7.9 min.1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-amine (17)

3 CH₂CH₃ I SFC w/AS column and 20% MeOH/0.1% DEA, 280 nm. 17 E1: HPLCR_(t) = 1.58 min; ¹H NMR (400 MHz, CDCl₃) 7.50 (d, J = 1.47 Hz, 1H),7.44 (d, J = 8.43 Hz, 1H), 7.29-7.27 (m, 1H), 3.01-2.97 (m, 1H), 2.44(d, J = 13.2 Hz, 1H), 2.21 (d, J = 13.2 Hz, 1H), 1.98-1.92 (m, 1H),1.79-1.25 (m, 8H), 1.09-1.03 (m, 4H); LC-MS 8.89 min, (M + 1)⁺ 286 @9.01 min. 17 E2: LC-MS 8.89 min, (M + 1)⁺ 288 @ 8.91 min. (±)1-(1-(4-chlorophenyl)cyclohexyl)propan-1-amine (18)

3 CH₂CH₃ I HPLC R_(t) = 8.68 min; LC-MS 7.91 min, (M + 1)⁺ 252 @ 8.04min. 1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (19)

3 CH₃ I Chiral HPLC with AD column and 100% MeOH/0.1% DEA, 280 nm 19 E1:HPLC R_(t) = 1.52 min; LC-MS (15 minute method) 8.18 min, (M + 1)⁺ 288 @8.35 min. 19 E2: LC-MS (15 minute method) 8.24 min, (M + 1)⁺ 288 @ 8.27min. 1-(1-(4-(furan-3-yl)phenyl)cyclohexyl)ethanamine (20)

3 CH₃ I SFC w/AD column and 35% MeOH/10% IPA/0.1% DEA, 25° C. columntemp., 10 ml/min total flow, 280 nm to give the fast moving enantiomerE1 and the slow moving enantiomer E2. 20 E1: ¹H NMR (400 MHz, CDCl₃)7.73 (s, 1H), 7.48-7.46 (m, 3H), 7.32 (d, J = 8.43 Hz, 2H), 6.70 (d, J =0.7 Hz, 1H), 2.77-2.72 (m, 1H), 2.37 (d, J = 13.2 Hz, 1H), 2.30 (d, J =13.2 Hz, 1H), 1.58-1.42 (m, 5H), 1.32-1.22 (m, 3H), 0.87 (d, J = 6.60Hz, 3H); LC-MS 7.94 min, (M + 1)⁺ 270 @ 8.06 min 20 E2: LC-MS 7.97 min,(M + 1)⁺ 270 @ 8.12 min1-(1-(4-chlorophenyl)cyclohexyl)-3-methylbutan-1-amine (21)

3 iso- butyl I SFC w/AS column and 15% IPA/0.1% DEA, 25° C. columntemp., 10 ml/min total flow, 280 nm to give the fast moving enantiomerE1 and the slow moving enantiomer E2. 21 E1: HPLC R_(t) = 9.26 min; ¹HNMR (400 MHz, CDCl₃); 7.31-7.23 (m, 4H), 2.57-2.54 (m, 1H), 2.32-2.23(m, 2H), 1.65-1.43 (m, 6H), 1.24- 1.13 (m, 4H), 0.93-0.78 (m, 7H),0.70-0.63 (m, 1H); LC-MS 9.01 min, (M + 1)⁺ 280 @ 9.19 min 21 E2: LC-MS9.01 min, (M + 1)⁺ 280 @ 9.19 min1-(1-(4-(furan-2-yl)phenyl)cyclohexyl)ethanamine (22)

3 CH₃ I SFC w/OD column and 12% MeOH/0.1% DEA, 40° C. column temp., 10ml/min total flow, 280 nm to give the fast moving enantiomer E1 and theslow moving enantiomer E2. 22 E1: HPLC R_(t) = 8.76 min; ¹H NMR (400MHz, CDCl₃) 7.66 (d, J = 8.54 Hz, 2H), 7.45 (d, J = 1.71 Hz, 1H), 7.34(d, J = 8.54 Hz, 2H), 6.63 (d, J = 3.42 Hz, 1H), 6.45 (dd, J = 1.71,3.42 Hz, 1H), 2.83 (bs, 1H), 2.39 (d, J = 12.7 Hz, 1H), 2.30 (d, J =11.7 Hz, 1H), 1.56-1.45 (m, 5H), 1.26 (bs, 3H), 0.90 (d, J = 6.35 Hz,3H); LC-MS 8.09 min, (M + 1)⁺ 270 @ 8.24 min. 22 E2: LC-MS 8.09 min,(M + 1)⁺ 280 @ 8.24 min.(1-(3′,5′-difluorobiphenyl-4-yl)cyclohexyl)methanamine (23)

3 H E HPLC R_(t) = 9.24 min; ¹H NMR (400 mHz, CD₃OD) 7.68-7.64 (m, 2H),7.51 (dd, J = 1.95, 8.96, 2H), 7.26-7.19 (m, 2H), 6.90-6.84 (m, 1H),3.03 (s, 2H), 2.28-2.24 (m, 2H), 1.67-1.36 (m, 8H). (±)1-(1-(4-(thiazol-2-yl)phenyl)cyclohexyl)ethanamine (24)

3 CH₃ I HPLC R_(t) = 1.50 min; LC-MS (15 minute method) 7.51 min, (M +1)⁺ 287 @ 7.72 min; ¹H NMR (400 MHz, CDCl₃) 7.95 (d, J = 8.43 Hz, 2H),7.85 (d, J = 3.30 Hz, 1H), 7.44 (d, J = 8.43 Hz, 2H), 7.32 (d, J = 3.30Hz, 1H), 3.13 (d, J = 6.23 Hz, 1H), 2.50 (d, J = 11.36 Hz, 1H), 2.33 (d,J = 12.10 Hz, 1H), 1.60-1.57 (m, 2H), 1.33-1.20 (m, 6H), 0.97-0.83 (m,3H). (±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)pentan-1-amine (25)

3 n-butyl I HPLC R_(t) = 1.68 min; LC-MS (15 minute method) 9.92 min,(M + 1)⁺ 316 @ 10.04 min; ¹H NMR (400 MHz, CDCl₃) 7.47-7.42 (m, 2H),7.26- 7.23 (m, 1H), 2.95 (d, J = 9.16 Hz, 1H), 2.38 (d, J = 12.10 Hz,1H), 2.23 (d, J = 12.83 Hz, 1H), 1.77-1.56 (m, 5H), 1.45 (s, 3H),1.28-1.14 (m, 6H), 0.78 (t, J₁ = 13.56 Hz, J₂ = 6.60 Hz, 3H). (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)heptan-1-amine (26)

3 n-hexyl I HPLC R_(t) = 1.78 min; LC-MS (15 minute method) 10.73 min,(M + 1)⁺ 344 @ 10.8 min; ¹H NMR (400 MHz, CDCl₃) 7.46-7.41 (m, 2H),7.26- 7.21 (m, 1H), 2.91 (d, J = 9.17 Hz, 1H), 2.36 (d, J = 12.46 Hz,1H), 2.23 (d, J = 13.20 Hz, 1H), 1.73-1.44 (m, 7H), 1.28-1.14 (m, 11H),0.82 (t, J₁ = 14.30 Hz, J₂ = 6.96 Hz, 3H).

The following compounds were synthesized from the respective cyclohexylnitrile according to General Procedure E, and were optionally convertedto the respective HCl salt form:

(1-(3,4-dichlorophenyl)cyclohexyl)-methanamine hydrochloride (27)

The title compound was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarbonitrile (920 mg, 3.62 mmol). Thecrude HCl salt was recrystallized from 1:5 CH₃CN/IPA (10 mL) to givepure [1-(3,4-Dichloro-phenyl)-cyclohexyl]-methylamine hydrochloride asan off-white solid. HPLC R_(t)=8.66 min; ¹H NMR (400 mHz, MeOH-d⁴)7.55-7.51 (m, 2H), 7.35-7.31 (dd, J=2.44, 8.55 Hz, 1H), 3.01 (s, 2H),2.17-2.12 (m, 2H), 1.65-1.28 (m, 8H); LCMS 8.52 min, (M+1)⁺ 258 @ 8.78min.

(1-(3-chlorophenyl)cyclohexyl)methanamine hydrochloride (28)

The title compound was synthesized from1-(3-chlorophenyl)-cyclohexanecarbonitrile (320 mg, 1.46 mmol). Thecrude HCl salt was recrystallized from CH₃CN (7.5 mL) to give pure(1-(3-chlorophenyl)cyclohexyl)-methanamine hydrochloride as off-whiteneedles/hay. HPLC R_(t)=8.18 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.41-7.26(m, 4H), 3.0 (s, 2H), 2.18-2.15 (m, 2H), 1.64-1.30 (m, 8H); LC-MS 7.72min, (M+1)⁺ 224 @ 8.0 min.

(1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride (29)

The title compound was synthesized from1-(4-chlorophenyl)-cyclohexanecarbonitrile. The crude HCl salt wasrecrystallized from CH₃CN (3 mL) to give pure(1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride as off-whiteneedles/hay. HPLC R_(t)=8.22 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.38 (s,4H), 2.97 (s, 2H), 2.19-2.14 (m, 2H), 1.63-1.30 (m, 8H); LC-MS 7.83 min,(M+1)⁺ 224 at 8.1 min.

(1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride (30)

The title compound was synthesized from1-(3,4-difluorophenyl)-cyclohexanecarbonitrile. The crude HCl salt wasrecrystallized from CH₃CN (6 mL) to give pure(1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride (38 mg, 17%)as off-white needles/hay HPLC R_(t)=8.06 min; ¹H NMR (400 mHz, MeOH-d⁴)7.34-7.20 (m, 3H), 2.99 (m, 2H), 2.15-2.12 (m, 2H), 1.64-1.31 (m, 8H);LC-MS 7.01 min, (M+1)⁺ 226 @ 7.16 min.

(1-phenylcyclohexyl)methaneamine hydrochloride (31)

The title compound was synthesized from1-phenylcyclohexane-carbonitrile. The crude HCl salt was recrystallizedfrom CH₃CN to give pure (1-phenylcyclohexyl)methaneamine hydrochlorideas off-white needles. HPLC R_(t)=7.59 min; ¹H NMR (400 mHz, MeOH-d⁴)7.40-7.36 (m, 4H), 7.27-7.25 (m, 1H), 2.98 (s, 2H), 2.22-2.20 (m, 2H),1.62-1.32 (m, 8H); LC-MS 6.16 min, (M+1)⁺ 190 @ 6.36 min.

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-methanamine (32)

The title compound was prepared from1-(3-chloro-4-fluorophenyl)cyclohexanecarbonitrile. A solution of thecrude product in MTBE was basicified at 0° C. with KOH, extracted withMTBE and evaporated. The residue was diluted in DCM, filtered through anaminopropyl column and evaporated to give the primary amine (64.1 mg,25%) as an oil. LCMS R_(t)=7.62 min, m/z=242 (M+1). ¹H NMR (CDCl₃, δ)7.34 (dd, J=2.4, 7.1 Hz, 1H), 7.19 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.11(t, J=8.7 Hz, 1H), 2.68 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79 (bs,2H). ¹³C NMR (CDCl₃, δ, mult): 157.4(0), 154.9(0), 142.2(0), 129.5(0),127.0(0), 126.9(1), 120.8(1), 120.6(1), 116.3(1), 116.1(1), 54.5(2),43.3(0), 33.7(2), 26.5(2), 22.0(2).

(1-(naphthalen-2-yl)cyclohexyl)methanamine (33)

The title compound was synthesized in 37% yield from1-(naphthalen-2-yl)cyclohexane-carbonitrile. HPLC R_(t) (5-100-8)=8.44min. LCMS R_(t)=8.22 min, m/z=240 (M+1). ¹H NMR (CDCl₃, δ): 7.9-7.2 (m,7H), 2.78 (s, 2H), 2.3 (m, 2H), 1.7-1.3 (m, 8H), 0.9 (bs, 2H). ¹³C NMR(CDCl₃, δ, mult): 133.4(0), 131.7(0), 128.0(1), 127.8(1), 127.3(1),126.4(1), 125.8(1), 125.4(1), 125.2(1), 54.6(2), 43.7(0), 33.8(2),26.7(2), 22.2(2).

(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (34)

The title compound was prepared from1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50mmol). The crude product was purified by silica gel columnchromatography (MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (62 mg, 48%) as aclear oil. ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H),1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49(d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.3, 26.7,34.8, 42.9, 54.4, 125.5, 125.6, 127.9, 129.9, 149.1. ESI MS m/z 258.

(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (35)

The title compound was prepared from1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (115 mg, 0.50 mmol).The crude product was purified by chromatography (SiO₂, MeOH/CH₂Cl₂,MeOH from 0% to 10%) to give (±)(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (58 mg, 50%) as aclear oil. ¹H NMR (CDCl₃) 1.34-1.39 (m, 3H), 1.46-1.54 (m, 7H),2.01-2.06 (m, 2H), 2.64 (s, 2H), 5.93 (s, 2H), 6.78 (s, 2H), 6.84 (s,1H). ¹³C NMR (CDCl₃) 22.3, 26.9, 34.3, 43.5, 54.9, 101.1, 107.9, 108.2,120.6, 138.7, 145.6, 148.2. ESI MS m/z 234.

(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (36)

The title compound was prepared from1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50mmol). The crude product was purified by chromatography (SiO₂,MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give (±)(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (26 mg, 20%) as aclear oil. ¹H NMR (CDCl₃): 1.26-1.41 (m, 5H), 1.50-1.63 (m, 5H),2.12-2.16 (m, 2H), 2.73 (s, 2H), 7.47-7.49 (m, 2H), 7.52-7.55 (m, 1H),7.58 (s, 1H). ¹³C NMR (CDCl₃) 22.3, 26.7, 33.8, 43.9, 54.6, 122.9,124.1, 124.2, 129.1, 130.8, 130.9, 146.3. ESI MS m/z 257.

(1-(3-fluorophenyl)cyclohexyl)methanamine (37)

The title compound was prepared from1-(3-fluorophenyl)cyclohexanecarbonitrile (102 mg, 0.50 mmol). The crudeproduct was purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0%to 10%) to give (±) (1-(3-fluorophenyl)cyclohexyl)methanamine (32 mg,31%) as a clear oil. ¹H NMR (CDCl₃): 1.26-1.39 (m, 5H), 1.51-1.58 (m,5H), 2.07-2.10 (m, 2H), 2.69 (s, 2H), 6.88-6.93 (m, 1H), 7.04 (d, J=8.0Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.27-7.34 (m, 1H). ¹³C NMR (CDCl₃)22.3, 26.8, 33.8, 43.9, 54.8, 112.7, 113.0, 114.5, 114.7, 123.0, 123.1,129.9, 130.0, 162.3, 164.7. ESI MS m/z 208.

(1-(2,4-dichlorophenyl)cyclohexyl)methanamine (38)

¹H NMR (400 MHz, CD₃Cl) δ 7.35 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.4 Hz,1H), 7.19 (dd, J=2.4, 8.4 Hz, 1H), 3.08 (s, 2H), 2.25 (m, 2H), 1.45 (m,2H), 1.31 (m, 2H), 1.28-1.18 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 139.91,134.39, 133.70, 132.89, 132.23, 48.61, 45.83, 33.70, 26.77, 26.66,22.56; ESI MS m/z 258.1.

(1-(6-fluoronaphthalen-2-yl)cyclohexyl)methanamine (39)

The title compound was synthesized according to Scheme 25, below.

To a solution of 6-fluoro-naphthalene-2-carboxylic acid (3.0 g, 15.8mmol) was added BH₃.THF (31.6 mL, 31.6 mmol). The reaction mixture wasstirred overnight before being concentrated. To the residue was addeddiethyl ether (100 mL) and NaOH solution (10 mL). The organic layer wasseparated, dried and concentrated. The resultant residue was purified bysilica gel column chromatography (ethyl acetate/hexane 1:7) to afford(6-fluoro-naphthalen-2-yl)-methanol (2.28 g, 82%).

To a solution of (6-fluoro-naphthalen-2-yl)-methanol (2.0 g, 11.3 mmol)in CH₂Cl₂ (30 mL) was added PBr₃ (1.0 M in CH₂Cl₂, 22.6 mmol). Thereaction mixture was stirred for 3 h at room temperature before beingquenched by NH₄Cl (30 mL). The organic layer was separated, dried andconcentrated. The resultant residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1:10) to afford2-bromomethyl-6-fluoro-naphthalene (2.23 g, 74%).

To a mixture of 2-bromomethyl-6-fluoro-naphthalene (1.5 g, 5.9 mmoL) inCH₃CN (30 mL) was added KCN (1.16 g, 17.8 mmoL). The reaction mixturewas heated at reflux for 6 h before being concentrated. To the residuewas added diethyl ether (100 mL) and H₂O (15 mL). The organic layer wasseparated, dried and concentrated. The resultant residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1:10) to affordthe (6-fluoro-naphthalen-2-yl)-acetonitrile (0.88 g, 70%).

The title compound was synthesized from(6-fluoro-naphthalen-2-yl)-acetonitrile (1.0 g, 5.48 mmoL) according toGeneral Procedure J to form the intermediate nitrile (0.98 g, 71%),which was purified by silica gel column chromatography (ethylacetate/hexane 1:7), followed by General Procedure E.

The crude product was dissolved in MeOH (4 mL) and subjected to reversephase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) togive the title compound (0.53 g, 75%). ¹H NMR (400 MHz, CD₃Cl) δ 8.29(m, 1H), 8.18 (m, 1H), 7.83 (m, 1H), 7.50 (dd, J=3.6, 6.8 Hz, 1H), 7.41(dd, J=6.0 Hz, 8.8 Hz, 1H), 7.06 (dd, J=8.8, 8.8 Hz, 1H), 3.37 (s, 2H),2.34 (m, 2H), 1.89 (m, 2H), 1.58 (m, 2H), 1.45 (m, 2H); ¹³C NMR (100MHz, CD₃Cl) δ 168.08, 159.85, 157.34, 132.96, 132.93, 128.58, 128.50,126.04, 125.69, 125.67, 125.63, 125.47, 125.35, 125.32, 122.44, 122.37,108.63, 108.44, 47.62, 43.53, 35.59, 26.43, 22.47, 22.31; ESI MS m/z258.1.

(1-(4-fluoronaphthalen-1-yl)cyclohexyl)methanamine (40)

The title compound was synthesized from4-fluoro-naphthalene-1-carboxylic acid (2.0 g, 10.3 mmol) according tothe synthetic procedures described above for the synthesis of 39 (Scheme25). The crude product was dissolved in MeOH (4 mL) and subjected toreverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to100%) to give 40 (0.51 g). ¹H NMR (400 MHz, CD₃OD) δ 8.48 (d, J=8.4 Hz,1H), 8.20 (d, J=8.4 Hz, 1H), 7.6 (m, 3H), 7.21 (dd, J=8.4, 8.4 Hz, 1H),3.67 (s, 2H), 2.52 (m, 2H), 2.04 (m, 2H), 1.68 (m, 2H), 1.50 (m, 4H);¹³C NMR (100 MHz, CD₃OD), δ 160.04, 157.54, 133.03, 132.99, 131.91,160.04, 157.54, 133.03, 132.99, 131.01, 128.74, 128.64, 126.64, 125.67,125.65, 125.51, 125.24, 125.22, 121.80, 121.73, 108.33, 108.14, 47.00,42.50, 35.12, 26.03, 21.89; ESI MS m/z 258.2.

1.3. Synthesis of Secondary and Tertiary Amines

Compounds in Table 2, below, were synthesized from the indicated primaryamine according to the indicated General Procedure and were optionallyconverted to the corresponding HCl salt form.

TABLE 2 Summary of Exemplary Secondary and Tertiary Amines GeneralPrepared Ar n R¹ R³ R⁴ Procedure From1-(1-(3,4-dichlorophenyl)cyclobutyl)-N,N-dimethylmethanamine (41)

1 H CH₃ CH₃ C 1 HPLC R_(t) = 8.42 min; ¹H NMR (400 mHz, MeOH-d⁴)7.58-7.53 (m, 2H), 7.34- 7.31 (m, 1H), 3.63 (s, 2H), 2.65 (s, 6H),2.49-2.29 (m, 4H), 2.07-1.87 (m, 2H); LC-MS 8.12 min, (M + 1)⁺ 258 @ 8.1min 1-(1-(3,4-dichlorophenyl)cyclobutyl)-N-methylmethanamine (42)

1 H H CH₃ A 1 HPLC R_(t) = 8.37 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.57 (d,J = 8.43 Hz, 1H), 7.44 (d, J = 1.83 Hz, 1H), 7.20 (dd, J = 2.2, 8.43 Hz,1H), 3.45 (s, 2H), 2.65 (s, 3H), 2.47-2.43 (m, 2H), 2.37-2.31 (m, 2H),2.22-2.15 (1H), 1.98-1.92 (m, 1H); LC-MS 7.1 min, (M + 1)⁺ 244 @ 7.28min. (±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylethanamine(43)

3 CH₃ CH₃ CH₃ C 2 HPLC R_(t) = 8.93 min; ¹H NMR (400 mHz, CDCl₃) 7.43(d, J = 1.83 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.22-7.19 (m, 1H), 2.54(d, J = 12.8 Hz, 1H), 2.44-2.40 (m, 1H), 2.09-2.05 (d, J = 13.9 Hz, 1H),1.95 (s, 6H), 1.56-1.48 (m, 5H), 1.25- 1.11 (m, 3H), 0.76 (d, J = 6.97Hz, 3H); LC-MS 10.2 min, (M + 1)⁺ 300 @ 10.26 min.1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E1)

3 CH₃ CH₃ CH₃ D 2 E1 HPLC R_(t) = 9.02 min; ¹H NMR (400 MHz, CD₃OD) 7.68(d, J = 2.2 Hz, 1H), 7.64-7.62 (m, 1H), 7.45 (dd, J = 2.2, 8.43 Hz, 1H),3.56-3.52 (m, 1H), 2.88 (s, 3H), 2.71 (d, J = 12.8 Hz, 1H), 2.36 (d, J =13.2 Hz, 1H), 2.19 (s, 3H), 1.70-1.60 (m, 5H), 1.38-1.25 (m, 5H),1.18-1.12 (m, 1H); LC-MS 9.55 min, (M + 1)⁺ 300 @ 9.84 min.1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E2)

3 CH₃ CH₃ CH₃ D 2 E2 LC-MS 9.47 min, (M + 1)⁺ 300 @ 9.64 min. (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,3-dimethylbutan-1-amine (45)

3 iso- butyl H CH₃ A 3 HPLC R_(t) = 9.57 min; ¹H NMR (400 MHz, CD₃OD)7.59 (d, J = 2.20 Hz, 1H), 7.54 (d, J = 8.80 Hz, 1H), 7.35 (dd, J =2.20, 8.43 Hz, 1H), 3.01-2.98 (m, 1H), 2.66 (s, 3H), 2.39 (m, 1H), 2.30(m, 1H), 1.97-1.46 (m, 7H), 1.31-1.22 (m, 3H), 1.12-1.06 (m, 2H), 0.84(d, J = 6.60 Hz, 3H), 0.70 (d, J = 6.60 Hz, 3H); LC-MS 8.93 min, (M +1)⁺ 328 @ 9.18 min. (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N,3-trimethylbutan-1-amine (46)

3 iso- butyl CH₃ CH₃ C 3 R_(t) = 9.72 min; ¹H NMR (400 MHz, CD₃OD) 8.05(bs, 1H), 7.48-7.46 (m, 1H), 7.40 (d, J = 8.43 Hz, 1H), 7.23 (dd, J =1.83-8.43 Hz, 1H), 2.62 (dd, J = 3.67, 9.16 Hz, 1H), 2.59-2.56 (m, 1H),2.30 (s, 6H), 2.19-2.16 (m, 1H), 1.61-1.11 (m, 12H), 0.88-0.85 (m, 6H);LC-MS 11.32 min, (M + 1)⁺ 342 @ 11.7 min. (±)1-(1-(4-methoxyphenyl)cyclohexyl)-N-methylethanamine (47)

3 CH₃ H CH₃ A 5 HPLC R_(t) = 8.22 min; ¹H NMR (400 MHz, CD₃OD) 7.30-7.26(m, 2H), 6.97- 6.94 (m, 2H), 3.76 (s, 3H), 3.09-3.04 (m, 1H), 2.57 (s,3H), 2.50-2.47 (m, 2H), 2.31-2.28 (m, 2H), 1.59-1.45 (m, 5H), 1.29-1.22(m, 3H), 1.09 (d, J = 6.60 Hz, 3H); LC-MS 5.57 min, (M + 1)⁺ 248 @ 6.07min 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E1)

3 CH₃ H CH₃ A 2 E1 HPLC R_(t) = 8.94 min; ¹H NMR (400 MHz, CD₃OD)7.61-7.58 (m, 2H), 7.36 (dd, J = 2.2, 8.43 Hz, 1H), 3.20-3.16 (m, 1H),2.65 (s, 3H), 2.51 (d, J = 12.5 Hz, 1H), 2.34 (d, J = 10.6 Hz, 1H),1.69-1.55 (m, 5H), 1.35-1.12 (m, 6H); LC-MS 7.08 min, (M + 1)⁺ 286 @7.46 min. [α]_(D) = −2.68 (c = 0.41, MeOH).1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E2)

3 CH₃ H CH₃ A 2 E2 LC-MS 7.03 min, (M + 1)⁺ 286 @ 7.58 min.1-(1-(biphenyl-4-yl)cyclohexyl)-N-methylmethanamine (49)

3 H H CH₃ A 8 HPLC R_(t) = 9.06 min; ¹H NMR (400 MHz, CD₃OD) 7.66 (d, J= 8.06 Hz, 2H), 7.59 (d, J = 8.43 Hz, 2H), 7.50 (d, J = 8.06 Hz, 2H),7.40 (d, J = 7.70 Hz, 2H), 7.31-7.29 (m, 1H), 3.14 (s, 2H), 2.54 (s,3H), 2.29-2.27 (m, 2H), 1.69-1.52 (m, 5H), 1.43-1.37 (m, 3H); LC-MS 7.05min, (M + 1)⁺ 280 @ 7.52 min. (±)1-(1-(4-chlorophenyl)cyclohexyl)-N-methylethanamine (50)

3 CH₃ H CH₃ A 11 HPLC R_(t) = 8.59 min; ¹H NMR (400 MHz, CD₃OD)7.43-7.34 (m, 4H), 3.14- 3.08 (m, 1H), 2.59 (d, J = 0.73 Hz, 3H),2.52-2.48 (d, J = 12.2 Hz, 1H), 2.33- 2.29 (d, J = 13.4 Hz, 1H),1.59-1.47 (m, 5H), 1.31-1.13 (m, 3H), 1.09 (d, J = 6.84 Hz, 3H); LC-MS7.10 min, (M + 1)⁺ 252 @ 7.32 min. (±)N-methyl-1-(1-(thiophen-2-yl)cyclohexyl)ethanamine (51)

3 CH₃ H CH₃ A 6 HPLC R_(t) = 7.92 min; ¹H NMR (400 MHz, CD₃OD) 7.42-7.40(m, 1H), 7.07- 7.04 (m, 1H), 7.01-6.99 (m, 1H), 3.17-3.10 (m, 1H), 2.61(s, 3H), 2.42-2.38 (m, 1H); 2.14-2.10 (m, 1H), 1.64-1.26 (m, 8H), 1.19(d, J = 6.59 Hz, 3H); LC-MS 5.80 min, (M + 1)⁺ 224 @ 6.19 min.N,N-dimethyl-1-(1-(4-(methylthio)phenyl)cyclohexyl)methanamine (52)

3 H CH₃ CH₃ C 10 HPLC R_(t) = 8.54 min; ¹H NMR (400 MHz, CD₃OD) 7.39 (d,J = 8.07 Hz, 2H), 7.30-7.28 (m, 2H), 3.34 (s, 2H), 2.52 (s, 6H), 2.43(s, 3H), 2.26-2.23 (d, J = 11.7 Hz, 2H), 1.66-1.52 (m, 5H), 1.38-1.37(m, 3H); LC-MS 6.97 min, (M + 1)⁺ 264 @ 7.16 min.N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (53)

3 H CH₃ CH₃ F 12 HPLC R_(t) = 8.96 min; ¹H NMR (400 MHz, CD₃OD)8.00-7.86 (m, 4H), 7.65 (dd, J = 2.2, 8.8 Hz, 1H), 7.54-7.51 (m, 2H),3.52 (s, 2H), 2.54 (s, 6H), 2.46-2.44 (d, J = 8.43 Hz, 2H), 1.84-1.50(m, 9H); LC-MS 8.28 min, (M + 1)⁺ 268 @ 8.39 min. (±)1-(1-(4-chlorophenyl)cyclohexyl)-N,2-dimethylpropan-1-amine (54)

3 iso- propyl H CH₃ F 14 HPLC R_(t) = 9.09 min; ¹H NMR (400 MHz, CD₃OD)7.40 (s, 4H), 2.99 (s, 1H), 2.67 (s, 3H), 2.45-2.38 (m, 2H), 2.17-2.14(m, 1H), 1.61-1.53 (m, 5H), 1.31-1.16 (m, 3H), 0.98 (d, J = 7.33 Hz,3H), 0.65 (d, J = 6.97 Hz, 3H); LC-MS 9.26 min, (M + 1)⁺ 280 @ 9.29 min.(±) N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (55)

3 CH₃ CH₃ CH₃ F 13 HPLC R_(t) = 9.04 min; ¹H NMR (400 MHz, CDCl₃)7.82-7.76 (m, 4H), 7.58-7.56 (m, 1H), 7.45-7.39 (m, 2H), 2.78 (d, J =12.5 Hz, 1H), 2.53-2.48 (m, 1H), 2.30 (d, J = 13.6 Hz, 1H), 1.94-1.18(m, 8H), 0.76 (d, J = 6.96 Hz, 3H); LC-MS 8.04 min, (M + 1)⁺ 282 @ 8.16min. N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E1)

3 CH₃ CH₃ CH₃ F 13 E1 HPLC R_(t) = 9.12 min; ¹H NMR (400 MHz, CD₃OD)8.03 (d, J = 1.1 Hz, 1H), 7.99 (d, J = 8.80 Hz, 1H), 7.96-7.93 (m, 1H),7.90-7.88 (m, 1H), 7.65 (dd, J = 1.83, 8.80 Hz, 1H), 7.56-7.51 (m, 2H),3.59 (q, J = 6.97, 13.9 Hz, 1H), 2.95-2.92 (m, 1H), 2.87 (s, 3H),2.59-2.56 (m, 1H), 2.0 (s, 3H), 1.76-1.19 (m, 11H); LC-MS 7.37 min, (M +1)⁺ 282 @ 7.60 min.N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E2)

3 CH₃ CH₃ CH₃ F 13 E2 LC-MS 8.42 min, (M + 1)⁺ 282 @ 8.57 min.N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (57)

3 H H CH₃ A 12 HPLC R_(t) = 8.65 min; ¹H NMR (400 MHz, CD₃OD) 8.67 (d, J= 8.8 Hz, 1H), 7.98 (d, J = 1.47 Hz, 1H), 7.96 (d, J = 1.83 Hz, 1H),7.89 (d, J = 8.43 Hz, 1H), 7.67-7.50 (m, 3H), 3.80 (bs, 2H), 2.63-2.58(s, 2H), 2.55 (s, 3H), 2.05-2.01 (bs, 2H), 1.69 (bs, 2H), 1.55 (bs, 3H);LC-MS 7.36 min, (M + 1)⁺ 254 @ 7.50 min.N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58 E1)

3 CH₃ H CH₃ A 13 E1 HPLC R_(t) = 8.93 min; ¹H NMR (400 MHz, CD₃OD)7.98-7.87 (m, 4H), 7.60-7.57 (m, 1H), 7.55-7.50 (m, 2H), 3.30 (1H,hidden), 2.76-2.72 (m, 1H), 2.64 (s, 3H), 2.59-2.55 (m, 1H), 1.69-1.60(m, 6H), 1.41-1.30 (m, 3H), 1.21 (d, J = 6.96 Hz, 3H); LC-MS 7.92 min,(M + 1)⁺ 268 @ 8.06 min.N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58 E2)

3 CH₃ H CH₃ A 13 E2 LC-MS 7.88 min, (M + 1)⁺ 268 @ 8.00 min.N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E1)

3 CH₃ H CH₃ A 16 E1 HPLC R_(t) = 1.56 min; LC-MS (5 minute method) 2.75min, (M + 1)⁺ 268 @ 2.84 min.; ¹H NMR (300 MHz, CD₃OD) 8.43 (s, 1H),8.33 (d, J = 8.80 Hz, 1H), 7.85 (t, 1H), 7.78 (d, J = 8.07 Hz, 1H), 7.56(d, J = 7.70 Hz, 1H), 7.45-7-38 (m, 2H), 4.05 (m, 1H), 2.52 (bs, 5H),1.82-1.78 (m, 2H), 1.75-1.48 (m, 4H), 1.32-1.06 (m, 5H).N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E2)

3 CH₃ H CH₃ A 16 E2 LC-MS (15 minute method) 7.19 min, (M + 1)⁺ 268 @7.52 min. N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (60E1)

3 CH₃ CH₃ CH₃ F 16 E1 HPLC R_(t) = 1.85 min; LC-MS (5 minute method)2.63 min, (M + 1)⁺ 282 @ 2.74 min.N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (60 E2)

3 CH₃ CH₃ CH₃ F 16 E2 LC-MS (15 minute method) 8.08 min, (M + 1)⁺ 282 @8.14 min.1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61 E1)

3 ethyl CH₃ CH₃ F 17 HPLC R_(t) = 1.61 min; LC-MS (15 minute method)11.91 min, (M + 1)⁺ 316 @ 12.08 min; ¹H NMR (300 mHz, CD₃OD) 8.40 (s,1H), 7.43-7.37 (m, 2H), 7.26-7.22 (m, 1H), 2.62 (d, J = 12.46, 1H),2.46-2.42 (m, 1H), 2.33 (s, 6H), 2.17 (d, J = 2.57, 1H), 1.63-1.46 (m,6H), 1.31-1.18 (m, 3H), 1.13-1.04 (m, 1H), 0.89 (t, 3H).1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61 E2)

3 ethyl CH₃ CH₃ F 17 E2 LC-MS (15 minute method) 11.90 min, (M + 1)⁺ 316@ 12.04 min. 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine(62 E1)

3 ethyl H CH₃ A 17 E1 HPLC R_(t) = 1.61 min; LC-MS (15 minute method)9.09 min, (M + 1)⁺ 302 @ 9.21 min; ¹H NMR (400 mHz, CDCl₃) 7.47-7.42 (m,2H), 7.25 (d, J = 7.70 Hz, 1H), 2.54 (s, 3H), 2.42-2.40 (m, 1H), 2.33(d, J = 13.20, 1H), 2.20 (d, J = 12.83, 1H), 1.76 (t, J = 11.73, 1H),1.68-1.57 (m, 5H), 1.36-1.14 (m, 4H), 0.89 (t, J = 7.33 Hz, 4H).1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62 E2)

3 ethyl H CH₃ A 17 E2 LC-MS (15 minute method) 9.31 min, (M + 1)⁺ 302 @9.36 min.N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (63E1)

3 CH₃ CH₃ CH₃ F 19 E1 HPLC R_(t) = 1.58 min; LC-MS (15 minute method)9.68 min, (M + 1)⁺ 316 @ 9.90 min. ¹H NMR (400 MHz, CDCl₃) 7.64 (d, J =8.80 Hz, 2H), 7.39 (d, J = 8.43 Hz, 2H), 4.85 (s, 3H), 3.59-3.53 (m,1H), 3.34-3.30 (m, 3H), 2.78 (d, J = 12.5 Hz, 1H), 2.40 (d, J = 13.2 Hz,1H), 1.73-1.59 (m, 5H), 1.40-1.34 (m, 2H), 1.27-1.25 (m, 3H), 1.16-1.15(m, 1H).N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (63E2)

3 CH₃ CH₃ CH₃ F 19 E2 LC-MS (15 minute method) 9.69 min, (M + 1)⁺ 316 @9.88 min.N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64 E1)

3 CH₃ H CH₃ A 19 E1 HPLC R_(t) = 1.52 min; LC-MS (15 minute method) 7.82min, (M + 1)⁺ 302 @ 7.94 min.; ¹H NMR (400 MHz, CD₃OD) 7.54 (d, J = 8.80Hz, 2H), 7.37 (d, J = 8.43 Hz, 2H), 3.19-3.14 (m, 1H), 2.64 (s, 3H),2.57 (d, J = 11.73 Hz, 1H), 2.39 (d, J = 12.83 Hz, 1H), 1.69-1.57 (m,5H), 1.37-1.22 (m, 3H), 1.14-1.13 (d, J = 6.6 Hz, 3H).N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64 E2)

3 CH₃ H CH₃ A 19 E2 LC-MS (15 minute method) 7.91 min, (M + 1)⁺ 302 @8.20 min.

The following compounds were synthesized from the corresponding primaryamine according to General Procedure F. The crude product was purifiedby silica gel column chromatography to give the respective mono- anddi-methylated products.

1-(1-(2,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (65)

The title compound was synthesized from 38. ¹H NMR (400 MHz, CD₃Cl) δ7.35 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.19 (dd, J=8.4, 2.4 Hz,1H), 3.00 (s, 2H), 2.31 (s, 3H), 2.31-2.28 (m, 2H), 1.83 (m, 2H), 1.56(m, 2H), 1.48-1.29 (m, 4H); ¹³C NMR (400 MHz, CD₃Cl) δ 140.61, 134.31,132.63, 132.53, 132.08, 126.99, 58.24, 44.40, 37.68, 34.44, 26.67,22.58; ESI MS m/z 272.07.

1-(1-(2,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (66)

The title compound was synthesized from 38. ¹H NMR (400 MHz, CD₃Cl) δ7.42 (d, J=8.8 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.0 Hz,1H), 3.04 (s, 2H), 2.40 (m, 2H), 2.18 (s, 6H), 1.80 (m, 2H), 1.54 (m,2H), 1.48-1.32 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 139.8, 134.27,133.03, 132.99, 132.07, 127.29, 65.40, 47.26, 44.12, 34.37, 26.37,22.34; ESI MS m/z 286.1.

1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N-methylmethanamine (67)

The title compound was synthesized from 39. ¹H NMR (400 MHz, CD₃Cl) δ8.55 (m, 1H), 8.19 (m, 1H), 7.56-7.40 (m, 2H), 7.30 (m, 1H), 3.22 (s,2H), 2.32 (m, 1H), 2.25 (s, 3H), 2.26 (m, 1H), 1.62 (m, 1H), 1.54-1.35(m, 5H); ¹³C NMR (400 MHz, CD₃Cl) 167.08, 159.65, 156.34, 132.86,132.83, 127.56, 127.49, 126.06, 125.92, 125.85, 125.83, 125.72, 125.32,125.29, 122.11, 122.03, 108.64, 108.45, 60.17, 44.42, 37.61, 36.73,35.90, 26.89, 26.82, 22.68, 22.73; ESI MS m/z 272.1.

1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N,N-dimethylmethanamine (68)

The title compound was synthesized from 39. ¹H NMR (400 MHz, CD₃Cl) δ8.47 (m, 1H), 8.17 (m, 1H), 7.50-7.44 (m, 2H), 7.08 (dd, J=10.0, 8.4 Hz,1H), 2.95 (m, 2H), 2.39 (m, 2H), 2.14 (m, 2H), 1.97 (s, 6H), 1.59 (m,2H), 1.44 (m, 2H); ¹³C NMR (100 MHz, CD₃Cl) 167.07, 158.95, 158.31,133.87, 132.73, 127.32, 127.23, 126.74, 126.72, 125.32, 125.00, 124.99,121.96, 121.90, 108.61, 108.41, 68.39, 48.40, 45.03, 37.61, 36.62,26.91, 22.74; ESI MS m/z 286.3.

1-(1-(4-fluoronaphthalen-1-ybcyclohexyl)-N-methylmethanamine (69)

The title compound was synthesized from 40. ¹H NMR (400 MHz, CD₃OD) δ8.5 (m, 1H) 8.19 (m, 1H), 7.5 (m, 3H), 7.10 (dd, J=8.4, 9.0 Hz, 1H),3.22 (s, 2H), 2.31 (m, 2H), 2.25 (s, 3H), 2.04 (m, 2H), 1.61 (m, 2H),1.44 (m, 4H); ¹³C NMR (100 MHz, CD₃OD) δ 159.26, 156.78, 136.59, 133.32,133.29, 159.26, 156.78, 136.59, 133.32, 133.29, 127.56, 127.48, 125.85,125.85, 125.31, 125.29, 122.11, 122.03, 108.64, 108.46, 60.13, 44.41,37.59, 36.72, 29.94, 26.89, 26.82, 22.72; ESI MS m/z 272.2.

1-(1-(4-fluoronaphthalen-1-yl)cyclohexyl)-N,N-dimethylmethanamine (70)

The title compound was synthesized from 40. ¹H NMR (400 MHz, CD₃OD) δ8.44 (m, 1H), 8.18 (m, 1H), 7.50 (m, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H),2.95 (s, 2H), 2.38 (m, 2H), 2.20 (m, 2H), 1.96 (s, 6H), 1.60 (m, 4H),1.44 (m, 2H); ¹³C NMR (100 MHz, CD₃OD), δ 159.06, 156.57, 133.53,127.22, 126.76, 126.73, 125.32, 125.00, 124.99, 121.96, 121.89, 108.00,108.43, 68.40, 48.42, 45.03, 36.63, 29.94, 26.92, 22.74; ESI MS m/z286.2.

1-(1-(3,4-dichlorophenyl)cyclohex-3-enyl)-N,N-dimethylmethanamine (72)

The title compound was synthesized according to Scheme 26, below.

(a) The primary amine 71 was synthesized from1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile according to GeneralProcedures Q, U, and E1. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J=8.4 Hz,1H), 7.39 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 5.75 (m, 1H), 5.64 (m, 1H),3.16 (d, J=12.8 Hz, 1H), 3.03 (d, J=12.8 Hz, 1H), 2.5 (d, J=16.8 Hz,1H), 2.23 (d, J=16.8 Hz, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H),1.74 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 140.55, 133.33, 131.96, 131.33,129.30, 127.53, 126.59, 123.44, 50.25, 39.35, 32.24, 30.58, 22.03; ESIMS m/z 256.1.

The title compound was synthesized from 71 according to GeneralProcedure D. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (broad, 1H), 7.41 (s, 1H),7.40 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.75 (m, 1H), 5.62 (m,1H), 3.02 (s, 2H), 2.64 (d, J=15.6 Hz, 1H), 2.45 (d, J=18.8 Hz, 1H),2.36 (s, 6H), 1.98 (m, 1H), 1.88 (m, 2H), 1.58 (m, 1H); ¹³C NMR (100MHz, CDCl₃), δ 144.16, 138.66, 132.99, 131.14, 130.70, 129.04, 127.36,126.53, 124.13, 69.27, 47.54, 46.45, 40.38, 33.04, 32.93, 21.99; ESI MSm/z 284.0.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine(Hydrochloride) (73)

(a) Synthesis of1-(3,4-dichlorophenyl)-N,N-diethylcyclohexane-carboxamide

The amide was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (232 mg, 0.85 mmol)and diethyl amine using General Procedure G and was isolated in 13%yield as a white solid. HPLC R_(t)=12.0 min; ¹H NMR (400 mHz, CDCl₃)7.38-7.26 (m, 2H), 7.08 (dd, J=2.2, 8.4 Hz, 1H), 3.29 (bs, 2H), 2.84(bs, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.73-1.54 (m, 7H), 1.29-1.24 (m, 2H),1.08 (bs, 3H), 0.82 (bs, 3H); ¹³C NMR (100 mHz, CDCl₃) 172.9, 147.2,133.0, 130.8, 130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7,13.4, 12.4; GC-MS (SCOUT) 13.2 min, M⁺ 327.

(b) Synthesis ofN-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine(Hydrochloride)

The title compound was synthesized from1-(3,4-dichlorophenyl)-N,N-diethylcyclohexanecarboxamide (19 mg, 0.058mmol) using General Procedure E followed by HCL salt formation. Thecrude HCl salt was recrystallized from EtOAc (1.5 mL) to give pure[1-(3,4-Dichloro-phenyl)-cyclohexylmethyl]-diethyl-amine hydrochlorideas an off-white solid. HPLC R_(t)=9.07 min; ¹H NMR (MeOH-d⁴) 7.65 (d,J=2.20 Hz, 1H), 7.55 (d, J=8.55 Hz, 1H), 7.43 (dd, J=2.2, 8.55 Hz, 1H),3.24 (s, 2H), 2.90-2.83 (m, 4H), 2.30-2.25 (m, 2H), 1.68-1.53 (m, 5H),1.35-1.24 (m, 3H), 1.10 (at, 6H); LCMS 10.8 min, (M+1)⁺ 314 @ 11.0 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine(Hydrochloride) (74)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexanecarboxamide

The amide was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (182 mg, 0.67 mmol)and dimethyl amine using General Procedure G and isolated in 36% yieldas a white solid. HPLC R_(t)=11.27 min; ¹H NMR (400 mHz, CDCl₃)7.36-7.34 (m, 2H), 7.06 (dd, J=2.2, 8.4 Hz, 1H), 2.71 (bs, 6H), 2.29 (d,J=12.1 Hz, 2H), 1.68-1.53 (m, 7H), 1.25-1.21 (m, 2H); ¹³C NMR (100 mHz,CDCl₃) 173.9, 146.9, 133.0, 130.9, 130.4, 127.4, 125.2, 51.0, 38.1,36.7, 25.9, 23.6; GC-MS (SCOUT) 12.8 min, M⁺ 299.

(b) Synthesis of1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine(Hydrochloride)

The title compound was synthesized from1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexanecarboxamide (71 mg, 0.24mmol) using General Procedure E followed by HCl salt formation. Thecrude HC 1 salt was recrystallized from CH₃CN (3 mL) to afford theproduct as an off-white solid. HPLC R_(t)=8.70 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.72 (d, J=2.44 Hz, 1H), 7.63 (d, J=8.55 Hz, 1H), 7.49 (dd,J=2.44, 8.55 Hz, 1H), 3.47 (bs, 2H), 3.32 (s, 6H), 2.28-2.24 (bs, 2H),1.81-1.39 (m, 8H); LCMS 9.79 min, (M+1)⁺ 286 @ 10.0 min.

Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine(Hydrochloride) (75)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N-methylcyclohexane-carboxamide

The amide was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (218 mg, 0.80 mmol)and methyl amine using General Procedure G and was isolated in 35% yieldas a white solid. HPLC R_(t)=10.3 min; ¹H NMR (400 mHz, CDCl₃) 7.47 (d,J=2.20 Hz, 1H), 7.41 (d, J=8.55 Hz, 1H), 7.24 (dd, J=2.44, 8.55 Hz, 1H),2.71 (d, J=4.88 Hz, 3H), 2.29-2.21 (m, 2H), 1.93-1.85 (m, 2H), 1.61-1.38(m, 6H); GC-MS (SCOUT) 12.87 min, M⁺ 285.

(b) Synthesis of1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (Hydrochloride)

The title compound was synthesized from1-(3,4-dichlorophenyl)-N-methylcyclohexanecarboxamide (80 mg, 0.28 mmol)using General Procedure E followed by HCL salt formation. The crude HClsalt was recrystallized from CH₃CN (3 mL) to give pure1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine hydrochlorideas an off-white solid. HPLC R_(t)=8.67 min; ¹H NMR (400 mHz, CDCl₃)7.57-7.54 (m, 2H), 7.34 (dd, J=2.2, 8.43 Hz, 1H), 3.12 (s, 2H), 2.54 (s,3H), 2.16-2.13 (m, 2H), 1.68-1.50 (m, 5H), 1.41-1.30 (m, 3H); LCMS 8.26min, (M+1)⁺ 272 @ 8.50 min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine(Hydrochloride) (76)

(a) 1-(3,4-dichlorophenyl)-N-ethyl-N-methyl-cyclohexane-carboxamide

The amide was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (390 mg, 1.43 mmol)and ethylmethylamine using General Procedure G and was isolated in 30%yield as a white solid. HPLC R_(t)=11.66 min; ¹H NMR (400 mHz, CDCl₃)7.40-7.30 (m, 2H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 3.31 (bs, 2H), 2.59(bs, 3H), 2.30 (d, J=12.5 Hz, 2H), 1.76-1.55 (m, 7H), 1.32-1.25 (m, 2H),1.00 (bs, 3H); ¹³C NMR (100 mHz, CDCl₃) 147.0, 132.9, 130.8, 130.3,127.5, 125.2, 51.0, 44.5, 36.8, 25.9, 23.5; GC-MS (SCOUT) 13.01 min, M⁺313.

(b) N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine

The title compound was synthesized from1-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclohexanecarboxamide (130 mg,0.414 mmol) using General Procedure E followed by HCl salt formation.The crude HC 1 salt was recrystallized from CH₃CN (3 mL) to give pureN-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine as whitecrystals. HPLC R_(t)=9.00 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.65 (d, J=2.2Hz, 1H), 7.56 (d, J=8.43 Hz, 1H), 7.42 (dd, J=2.2, 8.43 Hz, 1H),3.43-3.40 (m, 1H), 2.96-2.94 (m, 2H), 2.48 (s, 3H), 2.24 (m, 2H),1.66-1.53 (m, 5H), 1.41-1.31 (m, 3H), 1.14 (t, 3H); LC-MS 10.07 min,(M+1)⁺ 300 @ 10.3 min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine hydrochloride(77)

(a) 1-(3,4-dichlorophenyl)-N-ethylcyclohexane-carboxamide

The amide was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (280 mg, 1.03 mmol)and ethylamine using General Procedure G and was isolated in 28% yieldas a white solid. HPLC R_(t)=10.61 min; ¹H NMR (400 mHz, CDCl₃) 7.44 (d,J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz, 1H), 7.21 (dd, J=2.2, 8.4 Hz, 1H),5.4 (bs, 1H), 3.21-3.14 (m, 2H), 2.25-2.20 (m, 2H), 1.86-1.79 (m, 2H),1.58-1.52 (m, 5H), 1.35-1.32 (m, 1H), 1.00 (at, 3H); ¹³C NMR (100 mHz,CDCl₃) 174.3, 144.8, 132.8, 130.9, 130.7, 128.7, 126.2, 50.5, 34.8,34.7, 25.7, 23.0, 14.8; GC-MS (SCOUT) 12.9 min, M⁺ 299.

(b) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine(Hydrochloride)

The title compound was synthesized from1-(3,4-dichlorophenyl)-N-ethylcyclohexanecarboxamide (86 mg, 0.286 mmol)using General Procedure E followed by HCl salt formation. The crude HC 1salt was recrystallized from CH₃CN (4.5 mL) to give pure (±)N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine hydrochloride ascolorless crystals. HPLC R_(t)=8.90 min; ¹H NMR (400 mHz, McOH-d⁴) 7.57(d, J=2.2 Hz, 1H), 7.54 (d, J=8.43 Hz, 1H), 7.34 (dd, J=2.2, 8.43 Hz,1H), 3.11 (s, 3H), 2.94-2.88 (q, 2H), 2.18-2.15 (m, 2H), 1.68-1.58 (m,5H), 1.51-1.30 (m, 3H), 1.17 (t, 3H); LC-MS 8.45 min, (M+1)⁺ 286 @ 8.7min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanaminehydrochloride (78)

(a) Synthesis of1-(3,4-dichlorophenyl)-N-cyclopropylcyclo-hexanecarboxamide

The title compound was synthesized from1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (372 mg, 1.37 mmol)and cyclopropylamine using General Procedure G and was isolated in 25%yield as a white solid. HPLC R_(t)=10.6 min; ¹H NMR (400 mHz, CDCl₃)7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.43 Hz, 1H), 7.23-7.21 (m, 1H), 5.49(bs, 1H), 2.62-2.59 (m, 1H), 2.25-2.20 (m, 2H), 1.84-1.78 (m, 2H),1.59-1.55 (m, 5H), 1.38-1.33 (m, 1H), 0.73-0.68 (m, 2H), 0.37-0.33 (m,2H); ¹³C NMR (100 mHz, CDCl₃) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6,126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC-MS (SCOUT) 13.5 min, M⁺ 311.

(b) Synthesis ofN-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanaminehydrochloride

The title compound was synthesized from1-(3,4-dichlorophenyl)-N-cyclopropylcyclohexane carboxamide (108 mg,0.35 mmol) using General Procedure E followed by HCl formation. Thecrude HCl salt was recrystallized from 3:1 EtOAc:CH₃CN (4 mL) and 1:1EtOAc:CH₃CN (3 mL) to give pureN-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)cyclopropanaminehydrochloride as white crystals. HPLC R_(t)=9.02 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.57-7.52 (m, 2H), 7.35 (dd, J=1.83, 8.43 Hz, 1H), 3.29 (s,2H), 2.56-2.54 (m, 1H), 2.16-2.13 (m, 2H), 1.67-1.30 (m, 8H), 0.78-0.74(m, 4H); LC-MS 10.6 min, (M+1)⁺ 298 @ 10.8 min.

Synthesis of (1-(3-chlorophenyl)cyclohexyl)-N-methylmethanaminehydrochloride (79)

General Procedure H:

A solution of 1-(3-chlorophenyl)cyclohexane-carbaldehyde (119 mg, 0.53mmol), methyl amine (291 μL, 0.58 mmol, 2.0 M in THF) and sodiumcyanoborohydride (100 mg, 1.59 mmol) in 1:1 MeOH:Triethylorthoformate (4mL) was shaken at RT overnight. The solution was poured into saturatedaqueous K₂CO₃ and washed with EtOAc (2×20 mL). The combined organicwashes were dried (Na₂SO₄), filtered and concentrated. The crudematerial was dissolved in Et₂O and HCl (1.5 mL, 2.0 M in Et₂O) wasadded. The reaction was concentrated and the HCl salt was recrystallizedfrom CH₃CN (4.5 mL) to give pure(1-(3-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride ascolorless crystals HPLC R_(t)=8.25 min; ¹H NMR (400 mHz, MeOH-d⁴)7.43-7.28 (m, 4H), 3.12 (s, 2H), 2.54 (s, 3H), 2.19-2.16 (m, 2H),1.67-1.30 (m, 8H); LC-MS 7.29 min, (M+1)⁺ 238 @ 7.50 min.

N-methyl(1-phenylcyclohexyl)methanamine (Hydrochloride) (80)

The title compound was synthesized from 1-phenylcyclohexane-carbaldehyde(126 mg, 0.67 mmol) and methyl amine (370 μL, 0.73 mmol, 2.0 M in THF)according to General Procedure H, followed by HCl salt formation. TheHCl salt was recrystallized from CH₃CN to give pureN-methyl(1-phenylcyclohexyl)methanamine hydrochloride (8 mg, 6%) ascolorless crystals. HPLC R_(t)=7.76 min; ¹H NMR (400 mHz, MeOH-d⁴)7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 3.11 (s, 2H), 2.50 (s, 3H),2.25-2.22 (m, 2H), 1.67-1.23 (m, 8H); LC-MS 6.37 min, (M+1)⁺ 204 @ 6.62min.

(1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride(81)

The title compound was synthesized from1-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (131 mg, 0.58 mmol) andmethyl amine (320 μL, 0.64 mmol, 2.0 M in THF) according to GeneralProcedure H, followed by HCl salt formation. The HCl salt wasrecrystallized from CH₃CN to give pure(1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride ascolorless crystals. HPLC R_(t)=8.15 min; ¹H NMR (400 mHz, MeOH-d⁴)7.36-7.21 (m, 3H), 3.11 (s, 2H), 2.55 (d, J=3.67 Hz, 3H), 2.15-2.12 (m,2H), 1.67-1.31 (m, 8H); LC-MS 7.04 min, (M+1)⁺ 240 @ 7.19 min.

(1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride(82)

The title compound was synthesized from1-(3-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (191 mg, 0.72mmol) using General Procedure E, followed by HCl salt formation. Thecrude HCl salt was recrystallized from 2:1 CH₃CN:EtOAc (4.5 mL) to givepure (1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanaminehydrochloride as an off-white solid (21 mg, 12%). HPLC R_(t)=8.41 min;¹H NMR (400 mHz, MeOH-d⁴) 7.51-7.30 (m, 4H), 3.26-3.24 (m, 2H), 2.54 (s,6H), 2.24-2.20 (m, 2H), 1.72-1.33 (m, 8h); LC-MS 8.16 min, (M+1)⁺ 252 @8.27 min.

(1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride(83)

The title compound was synthesized from1-(3,4-difluorophenyl)-N,N-dimethylcyclohexanecarboxamide (195 mg, 0.73mmol) using General Procedure E (the amide was prepared from thecorresponding carboxylic acid according to General Procedure G),followed by HCl salt formation. The crude HCl salt was recrystallizedfrom 1:1 CH₃CN:EtOAc (3.0 mL) to give pure(1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochlorideas an off-white solid (16 mg, 8%). HPLC R_(t)=8.24 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.51-7.46 (m, 1H), 7.37-7.34 (m, 2H), 3.31-3.30 (m, 2H), 2.62(s, 6H), 2.26-2.23 (m, 2H), 1.78-1.38 (m, 8H); LC-MS 7.69 min, (M+1)⁺254 @ 7.91 min.

(1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride (84)

The title compound was synthesized from1-(4-chlorophenyl)-N-methylcyclohexanecarboxamide (278 mg, 1.11 mmol)using General Procedure E, followed by HCl salt formation to give pure(1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as anoff-white solid (185 mg, 70%). HPLC R_(t)=8.38 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.39 (s, 4H), 3.10 (s, 2H), 2.52 (s, 3H), 2.19-2.16 (m, 2H),1.65-1.49 (m, 6H), 1.37-1.30 (m, 4H); LC-MS 7.49 min, (M+1)⁺ 238 @ 7.63min.

(1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (85)

The title compound was prepared from1-(4-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (241 mg, 0.91mmol) according to General Procedure E. The crude product was purifiedby preparative TLC with 10% MeOH/CH₂Cl₂ (R_(f)=0.74) to give(1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine free base (11 mg,5%) as a clear oil. HPLC R_(t)=8.55 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.30(q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H), 1.97 (s, 6H), 1.60-1.25 (m,10H); LC-MS 8.09 min, (M+1)⁺ 252 @ 8.15 min.

N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride (86)

The title compound was synthesized fromN,N-dimethyl-1-phenylcyclohexanecarboxamide (200 mg, 0.87 mmol) usingGeneral Procedure E, followed by HCl salt formation. The crude HCl saltwas rechrystallized from 2:1 EtOAc:CH₃CN to giveN,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride as ananalytically pure off-white solid (8 mg, 4%). HPLC R_(t)=8.55 min; ¹HNMR (400 mHz, MeOH-d⁴) 7.30 (q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H),1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS 8.09 min, (M+1)⁺ 252 @ 8.15 min.HPLC R_(t)=8.03 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.48-7.39 (m, 4H),7.29-7.28 (m, 1H), 3.34 (d, J=2.57 Hz, 2H), 2.46 (d, J=3.30 Hz, 6H),2.29-2.26 (m, 2H), 1.67-1.39 (m, 8H); LC-MS 6.62 min, (M+1)⁺ 218 @ 6.80min.

(1-(3,4-dichlorophenyl)cyclopentyl)methanamine (87)

General Procedure G1—Amidation with Oxalyl Chloride:

To a solution of 1-(3,4-dichlorophenyl)cyclopentanecarboxylic acid (200mg, 0.7718 mmol) in DCM (lmL) and DMF (lmL) was added oxalyl chloride(1.54 mL, 1M in DCM) dropwise. After five minutes, the volatiles wereremoved in vacuo and the residual oil was dissolved in 2M ammonia (inethanol). After five minutes, the solvent was again removed, and theresidual oil was partitioned between MTBE and aqueous potassiumbicarbonate. After drying (sodium sulfate), the solvent was removed togive the crude amide.

The title compound was synthesized from the above amide using GeneralProcedure E. The crude product was purified by reverse-phase preparativeHPLC to give the primary amine (20 mg, 11% yield) as a pale-yellow oil.LCMS R_(t)=7.92 min, m/z=244 (M+1). ¹H NMR (CDCl₃, δ): 7.35 (m, 2H),7.11 (dd, J=2.2, 8.4 Hz, 1H), 2.72 (s, 2H), 2.0-1.6 (m, 8H), 1.1 (s,2H). ¹³C NMR (CDCl₃, δ, mult): 147.9(0), 132.1(0), 129.9(0), 129.7(1),129.3(1), 126.7(1), 51.7(2), 35.2(2), 23.4(2).

(1-(3,4-dichlorophenyl)cyclopentyl)-N-methylmethanamine (88)

The title compound was synthesized from1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and methyl amineusing General Procedure G1, followed by General Procedure E in 49%yield. LCMS R_(t)=11.16 min, m/z=258 (M+1). ¹H NMR (CDCl₃, δ): 7.4 (m,2H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 2.65 (s, 2H), 2.34 (s, 3H), 2.1-1.6(m, 8H). ¹³C NMR (CDCl₃, δ, mult): 148.3(0), 132.1(0), 129.9(1),129.7(0), 129.1(1), 126.5(1), 62.1(2), 51.6(0), 37.3(3), 36.2(2),23.5(2).

(1-(3,4-dichlorophenyl)cyclopentyl)-N,N-dimethylmethanamine (89)

The title compound was synthesized from1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and dimethyl amineusing General Procedure G1, followed by General Procedure E in 87%yield. LCMS R_(t)=8.69 min, m/z=272 (M+1). ¹H NMR (CDCl₃, δ): 7.40 (d,J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H),2.43 (s, 2H), 20.1 (s, 6H), 2.0-1.6 (m, 8H). ¹³C NMR (CDCl₃, δ, mult):149.2(0), 129.5(0), 129.2(1), 126.7(1), 131.6(1), 69.3(2), 52.1(0),48.0(3), 36.0(2), 23.2(2).

1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (90)

(a) Synthesis of 1-(4-fluorophenyl)-N-methylcyclohexanecarboxamide

The title compound was synthesized from1-(4-fluorophenyl)cyclohexane-carboxylic acid (222 mg, 1 mmol) andmethylamine (1 mL, 1M in THF, 1 eq) according to General Procedure G.The crude product was purified by silica gel column chromatography togive the amide (202.6 mg, 86%) as a white solid.

(b) Synthesis of 1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine

The title compound was synthesized from the above amide (100 mg, 0.43mmol) according to General Procedure E to give1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (61.6 mg, 66%) as aclear oil. LCMS R_(t)=6.62 min, m/z=222 (M+1). ¹H NMR (CDCl₃, δ): 7.30(dd, J=5.4, 8.9 Hz, 2H), 6.97 (t, J=8.8 Hz, 2H), 2.58 (s, 2H), 2.57 (s,3H), 2.1 (m, 2H), 1.7-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 162.1(0),159.7(0), 141.0(0), 128.5(1), 128.4(1), 115.1(1), 114.9(1), 64.6(2),41.8(0), 37.3(3), 34.7(2), 26.6(2), 22.1(2).

(1-(4-fluorophenyl)cyclohexyl)methaneamine (91)

The title compound was synthesized from1-(4-fluorophenyl)-cyclohexane-carboxylic acid and ammonia using GeneralProcedure G, followed by General Procedure E in 99% yield as a clearoil. LCMS R_(t)=6.76 min, m/z=208 (M+1). ¹H NMR (CDCl₃, δ): 7.24 (ddd,J=3.2, 5.4, 12.2 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 2.67 (s, 2H), 2.1 (m,2H), 1.6-1.2 (m, 8H), 0.79 (bs, 2H). ¹³C NMR (CDCl₃, δ, mult): 162.1(0),159.7(0), 140.3(0), 128.7(1), 128.6(1), 115.1(1), 114.9(1), 54.8(2),43.2(0), 33.8(2), 26.6(2), 22.1(2).

(1-(4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (92)

The title compound was synthesized from1-(4-fluorophenyl)cyclohexane-carboxylic acid and dimethyl amine usingGeneral Procedure G, followed by General Procedure E in 9% yield as asolid. LCMS R_(t)=7.22 min, m/z=236 (M+1). ¹H NMR (CDCl₃, δ): 7.32 (dd,J=5.5, 8.9 Hz, 2H), 6.99 (t, J=8.8 Hz, 2H), 2.30 (s, 2H), 2.1 (m, 2H),1.97, (s, 6H), 1.7-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 162.0(0),159.6(0), 141.7(0), 128.8(1), 128.7(1), 114.7(1), 114.5(1), 72.9(2),56.5(0), 48.4(3), 34.3(2), 26.6(2), 22.1(2).

N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine (93)

The title compound was synthesized from1-(naphthalen-2-yl)cyclohexane-carboxylic acid and methyl amine usingGeneral Procedure G, followed by General Procedure E in 74% yield as aclear oil. LCMS R_(t)=7.66 min, m/z=254 (M+1). ¹H NMR (CDCl₃, δ): 7.82(m, 4H), 7.54 (dd, J=1.8, 8.7 Hz, 1H), 7.45 (m, 2H), 2.69 (s, 2H), 2.3(m, 2H), 2.25 (m, 3H), 1.8-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult):142.7(0), 133.4(0), 131.7(0), 128.0(1), 127.9(1), 127.2(1), 126.1(1),125.7(1), 125.4(1), 125.0(1), 64.4(2), 42.4(0), 37.3(3), 34.7(2),26.7(2), 22.3(2).

N,N-dimethyl(1-(naphthalen-2-yl)-cyclohexyl)methanamine (94)

The title compound was synthesized from1-(naphthalen-2-yl)cyclohexane-carboxylic acid and dimethyl amine usingGeneral Procedure G, followed by General Procedure E and was obtained in11% yield as a clear oil. LCMS R_(t)=6.47 min, m/z=268 (M+1). ¹H NMR(CDCl₃, δ): 7.80 (m, 4H), 7.55 (dd, J=1.7, 8.6 Hz, 1H), 7.45 (m, 2H),2.2 (m, 2H), 1.97 (s, 6H), 1.8-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult):133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5, 125.1,72.6, 56.6, 48.4, 34.3, 26.6, 22.3.

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N-methylmethanamine (95)

General Procedure H1—Reductive Amination:

To a solution of 1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde (100mg, 0.4154 mmol) in methylamine (2.1 mL, 2M in THF, 10 eq) was addedacetic acid (104 ul, 5% of volume), and methanol was added until thesolution became clear. The solution was stirred for two hours. To thesolution was added sodium borohydride (40 mg, 3 eq) and stirring wascontinued for 30 minutes. The reaction was quenched with aqueouspotassium carbonate and extracted with MTBE. The organic phase wasseparated and the solvent removed in vacuo. The residue was redissolvedin MTBE and extracted with 3M HCl. The aqueous phase was separated,chilled in ice, and basicified with KOH. The aqueous phase was thenextracted with MTBE and the solvent removed in vacuo. The residue wasdiluted in DCM, filtered through aminopropyl cartridge. The solvent wasagain removed to give the secondary amine (75.1 mg, 71%) as a clear oil.LCMS R_(t)=7.39 min, m/z=256 (M+1). ¹H NMR (CDCl₃, δ): 7.34 (t, J=8.2Hz, 1H), 7.15 (dd, J=2.2, 11.4 Hz, 1H), 7.09 (dd, J=1.9, 8.4 Hz, 1H),2.58 (s, 2H), 2.28 (s, 3H), 2.0 (m, 2H), 1.7-1.3 (m, 8H). ¹³C NMR(CDCl₃, δ, mult): 159.4(0), 156.9(0), 147.2(0), 147.1(0), 130.2(1),123.5(1), 123.5(1), 118.0(0), 117.8(0), 115.6(1), 115.4(1), 64.2(2),42.3(0), 37.3(3), 34.5(2), 26.4(2), 22.1(2).

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N-methylmethanamine (96)

The title compound was synthesized from1-(3-chloro-4-fluorophenyl)-cyclohexanecarbaldehyde and methyl amineusing General Procedure H1 and was obtained in 55% yield. LCMSR_(t)=7.73 min, m/z=256 (M+1). ¹H NMR (CDCl₃, δ): 7.37 (dd, J=2.4, 7.1Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H),2.58 (s, 2H), 2.29 (s, 3H), 2.0 (m, 2H), 1.7-1.2 (m, 8H). ¹³C NMR(CDCl₃, δ, mult): 157.4(0), 154.9(0), 142.9(0), 129.2(1), 126.8(1),126.7(1), 120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0),37.3(3), 34.6(2), 26.4(2), 22.1(2).

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (97)

The title compound was synthesized from1-(3-chloro-4-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amineusing General Procedure H1 and was obtained in 88% yield as an oilysolid. The title compound was also synthesized from1-(1-(3-chloro-4-fluorophenyl)-cyclohexyl)-N-methylmethanamine accordingto General Procedure C.

LCMS R_(t)=8.81 min, m/z=270 (M+1). ¹H NMR (CDCl₃, δ): 7.38 (dd, J=2.4,7.2 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H),2.29 (s, 2H), 2.0 (m, 2H), 1.99 (s, 6H), 1.7-1.2 (m, 8H). ¹³C NMR(CDCl₃, δ, mult): 157.2(0), 154.7(0), 143.4(0), 129.6(1), 127.1(1),127.1(1), 120.3(0), 120.1(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3),43.0(0), 34.1(2), 26.4(2), 22.0(2).

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-methanamine (98)

The title compound was synthesized from1-(4-chloro-3-fluorophenyl)-cyclohexanecarbonitrile using GeneralProcedure E and was obtained in 19% yield as a clear oil. HPLCR_(t)=8.28 min. LCMS R_(t)=8.13 min, m/z=242 (M+1). HCl salt—¹H NMR(DMSO-d6, δ): 7.35 (t, J=8.1 Hz, 1H), 7.17 (d, J=11.3 Hz, 1H), 7.10 (d,J=8.4 Hz, 1H), 2.82 (s, 2H), 2.1 (m, 2H), 1.7-1.1 (m, 8H). ¹³C NMR(DMSO-d6, δ, mult): 159.2(0), 156.7(0), 143.1(0), 143.0(0), 130.6(1),124.1(1), 124.1(1), 118.5(0), 118.3(0), 116.2(1), 116.0(1), 50.2(2),40.6(0), 33.3(2), 25.5(2), 21.4(2).

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (99)

The title compound was synthesized from1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amineusing General Procedure H1 and was obtained in 97% yield. LCMSR_(t)=9.07 min, m/z=270 (M+1). ¹H NMR (CDCl₃, δ): 7.31 (t, J=8.2 Hz,1H), 7.17 (dd, J=2.1, 11.7 Hz, 1H), 7.09 (dd, J=1.8, 8.5 Hz, 1H), 2.30(s, 2H), 2.0 (m, 2H), 1.99 (s, 3H), 1.7-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ,mult): 159.2(0), 156.7(0), 147.8(0), 129.7(1), 123.9(1), 123.8(1),117.5(0), 117.3(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.3(0),34.1(2), 26.4(2), 22.1(2).

N-methyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (100)

(a) Preparation of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbonitrile

The title compound was synthesized from2-(4-(trifluoromethyl)phenyl)-acetonitrile (4.11 g, 22.2 mmol) and1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General ProcedureJ and was obtained as a clear oil (4.98 g, 89%). ¹H NMR (CDCl₃) δ1.23-1.39 (m, 1H), 1.76-1.92 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.63 (s,4H). ¹³C NMR (CDCl3) δ 23.7, 25.0, 37.4, 44.7, 122.2, 126.0, 126.7,130.2, 145.6, GC-MS m/z 253.

(b) Preparation of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde

General Procedure M:

To a solution of 1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile(4.80 g, 18.95 mmol) in toluene (60 ml) at −70° C. was dropwise added 1M DIBAL in hexane (38 ml, 38 mmol) over 30 min. The mixture was stirredat −70° C. for 30 min and for another 4 h at room temperature, whereuponethyl formate (3 ml) was added. The mixture was stirred at roomtemperature for 1 hour and was then poured into saturated NH₄Cl solution(70 ml). After 30 min, 2 M aqueous H₂SO₄ (100 ml) was added and theproduct was extracted with hexanes (3×100 ml). The combined organicphases were dried over MgSO₄ and evaporated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/hexanes, EtOAc from0% to 25%) to give 1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde(3.0 g, 65%) as clear oil. ¹H NMR (CDCl₃): δ 1.29-1.37 (m, 1H),1.46-1.55 (m, 2H), 1.59-1.69 (m, 3H), 1.83-1.90 (m, 2H), 2.29-2.34 (m,2H), 7.45 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 9.40 (s, 1H). ¹³CNMR (CDCl₃) δ 22.9, 25.6, 31.5, 54.7, 125.9, 126.0, 127.8, 129.5, 144.2,202.0.

(c) Preparation ofN-methyl(1-(4-(trifluoromethyl)phenyl)cyclohexyl)-methanamine

General Procedure H2—Reductive Amination:

A mixture of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde (256mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) in1,2-dichloroethane was stirred at room temperature for 30 min and wasthen treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol). Thereaction mixture was stirred at room temperature overnight and was thenquenched with aqueous saturated NaHCO₃ solution (10 ml). The product wasextracted with EtOAc (3×10 ml). The combined organic layers were driedover MgSO₄ and evaporated in vacuo. The residue was purified by silicagel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 20%) to giveN-methyl-1-(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (178 mg,66%). ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73(m, 2H), 2.13-2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49 (d, J=8.0Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). ¹³C NMR (CDCl3) δ 22.3, 26.7, 34.7,37.5, 42.9, 64.5, 125.4, 125.9, 127.6, 128.3, 150.2. ESI MS m/z 271.

N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine(101)

The title compound was prepared from1-(4-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50mmol) and dimethylamine (2.0 M in THF, 0.5 ml, 1.0 mmol) according toGeneral Procedure H2. The crude product was purified by silica gelcolumn chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to giveN,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (47mg, 33%). ¹H NMR (CDCl₃): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H),1.62-1.68 (m, 2H), 1.97 (s, 6H), 2.13-2.18 (m, 2H), 2.35 (s, 2H), 7.49(d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.4, 26.7,34.4, 37.5, 43.9, 48.6, 72.8, 123.3, 125.0, 125.1, 126.0, 127.6, 127.9,128.3, 150.8. ESI MS m/z 286.

1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine (102)

(a) Synthesis of 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile

The title compound was prepared according to General Procedure J to give1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (2.90 g, 57%) as awhite solid. ¹H NMR (CDCl₃): δ 1.24-1.35 (m, 1H), 1.74-1.88 (m, 7H),2.16 (d, J=11.2 Hz, 2H), 5.97 (s, 2H), 6.79 (d, J=8.0 Hz, 1H), 6.95-6.99(m, 2H). ¹³C NMR (CDCl₃) δ 23.7, 25.0, 37.5, 44.6, 122.5, 122.6, 124.9,125.0, 129.5, 129.7, 142.8.

(b) Preparation of 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde

The title compound was prepared from the above nitrile according toGeneral Procedure M. The crude product was purified by silica gel columnchromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (1.65 g, 56%) as awhite solid. ¹H NMR (CDCl₃): δ 1.25-1.34 (m, 1H), 1.41-1.50 (m, 2H),1.57-1.70 (m, 3H), 1.73-1.80 (m, 2H), 2.23-2.30 (m, 2H), 5.94 (s, 2H),6.75-6.82 (m, 3H), 9.30 (s, 1H). ¹³C NMR (CDCl₃) δ 23.0, 25.8, 31.7,54.1, 101.4, 107.8, 108.7, 120.8, 133.7, 146.9, 148.5, 202.1.

(c) 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-1N,N-dimethylmethanamine

The title compound was prepared from the above1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol)and dimethylamine (2.0 M in THF, 1.0 ml, 2.0 mmol) according to GeneralProcedure H2. The crude product was purified by silica gel columnchromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine (47mg, 33%) as clear oil. ¹H NMR (CDCl₃): δ 1.31-1.41 (m 3H), 1.42-1.53 (m,3H), 1.56-1.63 (m, 2H), 2.01 (s, 6H), 2.03-2.08 (m, 2H), 2.30 (s, 2H),5.91 (s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.82 (dd, J=8.0 Hz, 1.6 Hz, 1H),6.87 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 22.4, 26.8, 34.7, 37.5, 43.2,48.2, 73.0, 100.9, 108.0, 108.2, 120.5, 140.3, 145.3, 147.8. ESI MS m/z262.

1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (103)

The title compound was prepared from1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol)and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) according to GeneralProcedure H2. The crude product was purified by silica gel columnchromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 20%) to give1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (218 mg,88%). ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73(m, 2H), 2.03-2.12 (m, 2H), 2.28 (s, 3H), 2.60 (s, 2H), 5.90 (s, 2H),6.75-6.86 (m, 2H), 6.90 (s, 1H). ¹³C NMR (CDCl₃) δ 22.3, 26.7, 35.2,37.4, 42.3, 64.8, 101.0, 107.6, 108.2, 120.3, 139.4, 145.6, 148.1. ESIMS m/z 248.

N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (104)

(a) Preparation of 1-(3-(trifluoromethyl)phenyl)cyclohexanecarbonitrile

The title compound was prepared from2-(3-(trifluoromethyl)phenyl)acetonitrile (3.463 ml, 22.2 mmol) and1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General ProcedureJ to yield 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.40g, 90%) as a clear oil. ¹H NMR (CDCl₃) δ 1.26-1.39 (m, 1H), 1.76-1.88(m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.51-7.60 (m, 3H), 7.73 (s, 1H). ¹³CNMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5,130.0, 142.8, GC-MS m/z 253.

(b) Preparation of 1-(3-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde

The title compound was prepared from the above1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.60 g, 22.1mmol) according to General Procedure M. The crude product was purifiedby silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to25%) to give 1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde (3.85g, 68%) as a clear oil. ¹H NMR (CDCl₃): δ 1.25-1.34 (m, 1H), 1.45-1.53(m, 2H), 1.59-1.67 (m, 3H), 1.80-1.87 (m, 2H), 2.31-2.35 (m, 2H),7.45-7.53 (m, 3H), 7.58 (s, 1H), 9.38 (s, 1H). ¹³C NMR (CDCl₃) δ 22.8,25.6, 31.5, 54.6, 123.9, 124.0, 124.3, 129.5, 130.9, 141.3, 148.5,202.0.

(c) Synthesis ofN-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine

The title compound was prepared from1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (116 mg, 0.5 mmol)and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to GeneralProcedure H2. The crude product was purified by silica gel columnchromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to giveN-methyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (50 mg,45%). ¹H NMR (CDCl₃): δ 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76(m, 2H), 2.12-2.18 (m, 2H), 2.29 (s, 3H), 2.66 (s, 2H), 7.45-7.48 (m,2H), 7.56-7.59 (m, 1H), 7.61 (s, 1H). ¹³C NMR (CDCl₃) δ 22.3, 26.7,34.6, 37.4, 42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7.ESI MS m/z 271.

N,N-dimethyl-1-(1-(3-(trifluoromethyl)-phenyl)cyclohexyl)-methanamine(105)

The title compound was prepared from1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according toGeneral Procedure H2. The crude product was purified by silica gelcolumn chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to giveN,N-dimethyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (74mg, 52%) as a clear oil. ¹H NMR (CDCl₃): δ 1.29-1.38 (m 3H), 1.48-1.57(m, 3H), 1.63-1.70 (m, 2H), 1.97 (s, 6H), 2.11-2.15 (m, 2H), 2.34 (s,2H), 7.41-7.43 (m, 2H), 7.56-7.59 (m, 1H), 7.63 (s, 1H). ¹³C NMR (CDCl₃)δ 22.4, 26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1,147.6, 150.8. ESI MS m/z 286.

1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (106)

(a) Preparation of 1-(3-fluorophenyl)cyclohexanecarbonitrile

The title compound was prepared from 2-(3-fluorophenyl)acetonitrile(2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol)according to General Procedure J to yield1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil.¹H NMR (CDCl₃) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz,1H), 7.30-7.35 (m, 1H). ¹³C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5,125.0, 125.1, 126.0, 129.5, 130.0, 142.8.

(b) Preparation of 1-(3-fluorophenyl)cyclohexanecarbaldehyde

The title compound was prepared from1-(3-fluorophenyl)cyclohexanecarbonitrile (3.52 g, 17.32 mmol) accordingto General Procedure M. The crude product was purified by silica gelcolumn chromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give1-(3-fluorophenyl)cyclohexanecarbaldehyde (2.01 g, 56%) as a clear oil.¹H NMR (CDCl₃): δ 1.29-1.37 (m, 1H), 1.44-1.53 (m, 2H), 1.58-1.67 (m,3H), 1.79-1.85 (m, 2H), 2.26-2.31 (m, 2H), 6.93-6.98 (m, 1H), 7.04 (d,J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H), 9.36 (s, 1H).¹³C NMR (CDCl₃) δ 22.9, 25.7, 31.5, 54.5, 114.4, 123.0, 130.5, 142.8,162.2, 164.7, 202.0.

(c) Synthesis of 1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine

The title compound was prepared from the above1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.5 mmol) andmethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to GeneralProcedure H2. The crude product was purified by silica gel columnchromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (50 mg, 45%). ¹HNMR (CDCl₃): 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H),2.12-2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H), 7.45-7.48 (m, 2H),6.87-6.92 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H),7.27-7.32 (m, 1H). ¹³C NMR (CDCl₃) 22.4, 26.8, 34.9, 37.5, 42.6, 64.6,112.7, 112.9, 114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7. ESI MSm/z 222.

1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (107)

The title compound was prepared from1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.50 mmol) anddimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to GeneralProcedure H2. The crude product was purified by column chromatography(SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (46 mg, 39%) asa clear oil. ¹H NMR (CDCl₃): δ 1.32-1.38 (m 3H), 1.49-1.56 (m, 3H),1.59-1.66 (m, 2H), 1.99 (s, 6H), 2.05-2.09 (m, 2H), 2.33 (s, 2H),6.83-6.88 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H),7.23-7.29 (m, 1H). ¹³C NMR (CDCl₃) δ 22.4, 26.8, 34.4, 43.6, 48.6, 72.9,112.2, 112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5. ESI MSm/z 236.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (108)

(a) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol

To a solution of 1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (440 mg,1.71 mmol) in anhydrous THF (17 mL) at 0° C. was added slowly methyllithium (1.6 M in Et₂O, 3.21 mL, 5.14 mmol). The solution was allowed towarm to RT and was stirred for 16 h. It was then quenched with MeOH (5mL). The crude reaction mixture was poured into 2M HCl (15 mL) andwashed with EtOAc (3×20 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated to give1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol. HPLC R_(t)=11.28 min; ¹HNMR (400 mHz, CDCl₃) 7.44-7.41 (m, 2H), 7.20 (dd, J=2.2, 8.4 Hz, 1H),3.63-3.58 (m, 1H), 2.39-2.35 (m, 1H), 2.14-2.10 (m, 1H), 1.67-1.48 (m,5H), 1.31-1.16 (m, 3H), 0.92 (d, J=6.6 Hz, 3H).

(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone

To a solution of crude 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol (494mg, 1.81 mmol) in CH₂Cl₂ (18 mL) was added Dess-Martin periodinane (997mg, 2.35 mmol). The resulting suspension was stirred at RT for 2 h andwas then concentrated. The crude ketone was purified by silica gelcolumn chromatography with an EtOAc/hexane gradient (product R_(f)=0.6in 10% EtOAc/hexanes) to give1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (312 mg, 67%) as an orangeoil. HPLC R_(t)=11.61 min; ¹H NMR (400 mHz, CDCl₃) 7.42-7.40 (m, 2H),7.15 (dd, J=2.2, 8.4 Hz, 1H), 2.32-2.29 (m, 2H), 1.92 (s, 3H), 1.80-1.74(m, 2H), 1.65-1.43 (m, 5H), 1.35-1.30 (m, 1H); ¹³C NMR (100 mHz, CDCl₃)209.5, 143.3, 133.2, 131.3, 130.9, 128.9, 126.3, 56.2, 33.7, 25.8 (2overlapping peaks), 23.2.

(c) Synthesis of(±)1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine hydrochloride

A mixture of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (247 mg, 0.91mmol) and methyl amine (455 μL, 2.0 M in THF, 0.91 mmol) was stirred atRT for 2 min. Titanium (IV) isoproxide (336 μL, 1.14 mmol) was thenadded. The viscous green/yellow solution was stirred at RT for 3 h.NaBH₃CN solution (640 μL, 1.0 M in MeOH, 0.64 mmol) was added and thecloudy solution was stirred at RT for 16 h. The solution was quenchedwith saturated NaCl solution (3 mL), filtered, and washed with MeOH (50mL). 6M HCl (20 mL) was added and the aqueous phase was washed with Et₂O(2×20 mL). The pH of the aqueous phase was adjusted to pH=12 with 3MNaOH and washed with EtOAc (3×30 mL). The combined organic phases weredried (Na₂SO₄), filtered and concentrated. To a solution of the crudeamine in Et₂O (3 mL) was added HCl (3 mL, 2.0 M in Et₂O). The crude HClsalt was recrystallized from CH₃CN (6 mL) at 110° C. to give1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (8 mg) as whitecrystals. HPLC R_(t)=8.90 min; ¹H NMR (400 mHz, CD₃OD) 7.57-7.53 (m,2H), 7.33-7.31 (m, 1H), 3.15-3.13 (m, 2H), 2.61 (s, 3H), 2.45 (broad d,J=11.73 Hz, 1H), 2.30 (broad d, J=12.46, 1H), 1.59-1.51 (m, 5H),1.31-1.08 (m, 6H); LC-MS 7.87 min, (M+1)⁺ 286 @ 8.10 min.

Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one (a)1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-ol

1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (519 mg, 2.01 mmol) wasdissolved in anhydrous THF (17 mL) and cooled to 0° C. Ethyl magnesiumchloride (2.0 M in THF, 3.03 mL, 6.06 mmol) was added slowly. Thesolution was allowed to warm to RT and stir for 16 h, then quenched withMeOH (5 mL). The crude reaction mixture was poured into 2M HCl (15 mL)and washed with EtOAc (3×20 mL). The combined organic washes were dried(Na₂SO₄), filtered and concentrated to give the secondary alcohol (443mg, 77% for 2 steps) as a white solid. HPLC R_(t)=11.65 min; ¹H NMR (400mHz, CDCl₃) 7.43-7.41 (m, 2H), 7.19 (dd, J=2.2, 8.4 Hz, 1H), 3.27-3.23(m, 1H), 2.37-2.33 (m, 1H), 2.17-2.14 (m, 1H), 1.57-1.46 (m, 6H),1.29-1.17 (m, 4H), 0.90-0.77 (m, 4H); ¹³C NMR (125 mHz, CDCl₃) 143.0,132.4, 130.9, 130.1, 130.0, 128.3, 81.7, 47.1, 32.6 (doublet), 26.7,24.4, 22.2, 11.4.

(b) 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one

The crude ethyl alcohol product (577 mg, 2.01 mmol) was dissolved inCH₂Cl₂ (20 mL) and Dess-Martin Periodinane (1.1 g, 2.61 mmol) was added.The white opaque suspension was stirred at RT for 2 h, thenconcentrated. The crude ketone was purified by silica gel columnchromatography with an EtOAc/hexane gradient (R_(f)=0.6 in 10%EtOAc/hexanes) to give the desired ethyl ketone (443 mg, 77%) as a whitesolid. HPLC R_(t)=12.0 min; ¹H NMR (400 mHz, CDCl₃) 7.44-7.38 (m, 2H),7.11 (dd, J=2.6, 8.4 Hz, 1H), 2.32-2.20 (m, 4H), 1.80-1.74 (m, 2H),1.68-1.42 (m, 5H), 1.34-1.26 (m, 2H), 0.90 (t, 3H); ¹³C NMR (125 mHz,CDCl₃) 212.1, 143.6, 133.1, 130.9, 130.8, 128.8, 126.3, 56.0, 33.7,30.7, 25.8, 23.3, 8.49. This compound can be used to synthesizecompounds of the invention with R¹=ethyl, e.g., through reductiveamination. Exemplary compounds include:

1.4. Synthesis of 3,4-dichlorophenyl Cyclohexylamines with Cyclic AmineSubstituents from Corresponding Carboxylic Acids

Compounds in Table 3, below, were synthesized from the correspondingcarboxylic acids via the amide intermediate according to GeneralProcedure G and General Procedure E.

TABLE 3 Summary of Exemplary Cyclic Amines1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)piperidine (109)

HPLC R_(t) = 9.20 min; ¹H NMR (400 MHz, MeOH-d⁴) 7.65 (s, 1H), 7.50 (d,J = 8.8 Hz, 1H), 7.43-7.41 (m, 1H), 3.22 (t, J = 1.47 Hz, 1H), 3.05-2.99 (m, 2H), 2.73- 2.67 (m, 2H), 2.22-2.18 (m, 2H), 1.71-1.26 (m, 14H);LC-MS 11.79 min, (M + 1)⁺ 326 @ 11.91 min.4-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)morpholine (110)

HPLC R_(t) = 8.82 min; ¹H NMR (400 MHz, MeOH-d⁴) 7.66 (d, J = 1.83 Hz,1H), 7.54 (d, J = 8.43 Hz, 1H), 7.43 (dd, J = 2.2, 8.43 Hz, 1H), 3.81-3.70 (m, 4H), 3.46 (s, 2H), 3.25-3.24 (m, 2H), 3.07-3.04 (m, 2H),2.93-2.88 (m, 2H), 2.24-2.20 (m, 2H), 1.78-1.70 (m, 2H), 1.61-1.31 (m,6H); LC-MS 11.09 min, (M + 1)⁺ 328 @ 11.28 min.1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)pyrrolidine (111)

HPLC R_(t) = 9.12 min; ¹H NMR (400 MHz, CDCl₃) 7.43 (d, J = 2.20 Hz,1H), 7.35 (d, J = 8.43 Hz, 1H), 7.22-7.20 (m, 1H), 2.52 (s, 2H), 2.23(s, 3H), 2.05-2.02 (m, 2H), 1.65-1.48 (m, 10H), 1.38-1.25 (m, 3H); LC-MS9.31 min, (M + 1)⁺ 312 @ 9.39 min.1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-4-methylpiperazine (112)

Prepared from Amide Intermediate 298 HPLC R_(t) = 9.47 min; ¹H NMR (400MHz, MeOH-d⁴) 7.64 (s, 1H), 7.49 (d, J = 8.43 Hz, 1H), 7.42 (d, J = 8.79Hz, 1H), 3.46 (bs, 4H), 3.10 (bs, 3H), 2.83 (s, 3H), 2.26-2.22 (m, 2H),1.73-1.67 (m, 2H), 1.57-1.28 (m, 7H); LC-MS 10.36 min, (M + 1)⁺ 341 @10.51 min. (±)1-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)-2,3-dihydro-1H-inden-2-ol (113)

HPLC R_(t) = 9.44 min; ¹H NMR (400 MHz, CDCl₃) 7.49 (d, J = 2.2 Hz, 1H),7.42 (d, J = 8.43 Hz, 1H), 7.26-7.13 (m, 4H), 6.91 (d, J = 6.97 Hz, 1H),4.35-4.32 (m, 1H), 3.90 (d, J = 5.13 Hz, 1H), 3.02-2.88 (m, 3H), 2.79(d, J = 11.7 Hz, 1H), 2.19-2.16 (m, 1H), 2.07-2.04 (m, 1H), 1.74-1.26(m, 9H); LC-MS 10.84 min, (M + 1)⁺ 390 @ 10.99 min. (±)1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-3-methylpiperidine (114)

HPLC R_(t) = 9.46 min; ¹H NMR (400 MHz, CD₃OD) 7.69 (dd, J = 1.83, 14.66Hz, 1H), 7.54 (d, J = 8.43 Hz, 1H), 7.49-7.44 (m, 1H), 3.51-3.41 (m,1H), 3.26-3.25 (d, J = 1.47 Hz, 1H), 3.06-2.90 (m, 3H), 2.73-2.58 (m,1H), 2.43-2.37 (m, 1H), 2.25 (bs, 2H), 1.96-1.29 (m, 11H), 1.08-0.96 (m,1H), 0.78 (m, 3H); LC-MS 11.95 min, (M + 1)⁺ 340 @ 12.18 min. (±)1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-2-methylpyrrolidine (115)

HPLC R_(t) = 9.25 min; ¹H NMR (400 MHz, CD₃OD) 7.64 (s, 1H), 7.55 (dd, J= 3.67, 8.43 Hz, 1H), 7.42 (d, J = 7.33 Hz, 1H), 3.52 (d, J = 13.6 Hz,1H), 3.25 (s, 2H), 3.00-2.98 (m, 1H), 2.69-2.65 (m, 1H), 2.37-2.34 (m,1H), 2.11 (bs, 2H), 1.91-1.23 (m, 14H); LC-MS 10.1 min, (M + 1)⁺ 326 @10.1 min. (±)2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclopentanol (116)

HPLC R_(t) = 8.86 min; ¹H NMR (400 MHz, CD₃OD) 7.58 (d, J = 2.57 Hz,1H), 7.53 (d, J = 8.43 Hz, 1H), 7.39-7.36 (m, 1H), 4.03-3.98 (m, 1H),3.40 (d, J = 13.2 Hz, 1H), 3.17-3.10 (m, 2H), 2.17-2.04 (m, 3H),1.95-1.89 (m, 1H), 1.71-1.32 (m, 12H); LC-MS 9.31 min, (M + 1)⁺ 342 @9.42 min. (±)2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclohexanol (117)

HPLC R_(t) = 9.1 min; ¹H NMR (400 MHz, CD₃OD) 7.60 (d, J = 2.20 Hz, 1H),7.60-7.52 (m, 1H), 7.41-7.37 (m, 1H), 3.48-3.43 (m, 1H), 3.15-3.11 (m,1H), 2.75-2.69 (m, 1H), 2.21-2.11 (m, 2H), 1.98-1.15 (m, 16H); LC- MS9.50 min, (M + 1)⁺ 356 @ 9.6 min.

Example 2 Synthesis of 2-Substituted Cycloalkylamines 2.1. Synthesis of2-Hydroxy-Substituted Cycloalkylamines

The below described compound of the invention were synthesized from thecorresponding bromomethyl analogs according to General Procedures 0 andP (outlined below).

cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (Cis 121)

cis 121 E1 cis 121 E2 (a) Preparation of Racemic(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)-cyclohexanol

General Procedure O:

A mixture of (cis)-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol(148 mg, 0.438 mmol) and sodium azide (85 mg, 1.314 mmol), in DMF (2 ml)was stirred at 70° C. for 48 hours. The reaction mixture was filteredand evaporated in vacuo. The residue was partitioned between water (5ml) and EtOAc (10 ml). The organic layer was separated, washed withwater (2×5 ml), dried over Na₂SO₄, and evaporated to give(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (110 mg, 84%)as a clear oil.

The enantiomers of(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol were separatedusing preparative HPLC (ChiralPak OJ column; hexanes:IPA=90:10; 8ml/min; λ=280 nm) to give cis 120 E1 (retention time=10.5 min) and cis120 E2 (retention time=13.7 min). The absolute configurations of thechiral centers were not determined. ¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H),1.43-1.54 (m, 3H), 1.67-1.75 (m, 4H), 2.00 (brs, 1H), 2.08-2.14 (m, 1H),3.43 (d, J=12.0 Hz, 1H), 3.65 (d, J=12.0 Hz, 1H), 4.04 (t, J=6.0 Hz,1H), 7.42 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 2.4 Hz, 1H), 7.75 (s, 1H).¹³C NMR (CDCl₃) δ 21.4, 22.8, 30.2, 30.4, 47.4, 59.8, 74.0, 127.9,130.6, 130.8, 131.2, 132.9, 142.7.

(b) Synthesis of cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanols

General Procedure P:

To a solution of cis 120 E1 (37 mg, 0.124 mmol) in EtOAc (2 ml) wasadded Pd/C (10%, 20 mg). A hydrogen balloon was attached and thereaction mixture was stirred at room temperature for 30 min. The mixturewas filtered and evaporated. The residue was purified by silica gelcolumn chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give theprimary amine cis 121 E1 (24 mg, 69%) as clear oil.

Cis 121 E2 was synthesized from cis 120 E2 (31 mg, 0.124 mmol) accordingto General Procedure P to give the primary amine (21 mg, 72%) as a clearoil.

¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m,1H), 1.78-1.83 (m, 2H), 1.98-2.02 (m, 1H), 2.91 (d, J=13.6 Hz, 1H), 3.07(d, J=13.6 Hz, 1H), 4.03 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40 (d, J=8.4 Hz,1H), 7.71 (dd, J=12.0, 2.4 Hz, 1H), 7.96 (s, 1H). ¹³C NMR (CD₃Cl): δ21.4, 24.6, 30.2, 35.2, 46.9, 56.3, 81.1, 129.3, 130.3, 130.4, 131.7,132.6, 142.7. ESI MS m/z 274.

trans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (Trans 121)

trans 121 E1 trans 121 E2

(a) Preparation of Racemic(trans)-2-(Azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

The title compound was prepared fromtrans-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (103 mg, 0.305mmol) and sodium azide (59 mg, 1.314 mmol) according to GeneralProcedure O to give the azide (70 mg, 76%) as a clear oil. Theenantiomers were separated as described to give trans 120 E1 (retentiontime=11.7 min) and trans 120 E2 (retention time=14.2 min). ¹H NMR(CDCl₃) δ 1.38-1.46 (m, 2H), 1.51-1.56 (m, 1H), 1.62-1.66 (m, 2H),1.71-1.76 (m, 1H), 1.80-1.93 (m, 3H), 3.43 (d, J=12.4 Hz, 1H), 3.81 (d,J=12.4 Hz, 1H), 4.24 (t, J=4.0 Hz, 1H), 7.25-7.28 (m, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.3, 21.6,29.7, 29.8, 46.8, 57.6, 71.3, 126.7, 129.4, 130.4, 130.6, 132.9, 146.5.

(b) Synthesis oftrans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

Trans 121 E1 and trans 121 E2 were prepared from trans 120 E1 and trans120 E2, respectively, according to General Procedure P. The crudeproducts were purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from0% to 15%) to give the primary amines (about 15 mg each, 65%) as clearoils.

¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m,1H), 3.02 (d, J=12.4 Hz, 1H), 3.38 (d, J=12.4 Hz, 1H), 4.20 (dd, J=10.0Hz, 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.69 (d, J=1.6 Hz, 1H). ¹³C NMR(CDCl₃) δ 21.5, 22.3, 29.9, 30.4, 44.8, 57.1, 71.5, 126.9, 129.6, 131.1,131.4, 133.3, 142.9. ESI MS m/z 274.

2.2. Synthesis of 2-Methoxy-Cycloalkylamines

The following compounds were synthesized according to the Scheme, below.

1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine (124)A. Synthesis ofcis-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine(Cis 124)

A solution of (±) cis 122 [Boc-protected (±)cis-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexanol] (0.88 g,2.27 mmol) and NaH (100 mg, 2.50 mmol) in THF (30 ml) was stirred atroom temperature for 30 min. To the mixture was added CH₃I (1.41 ml,22.7 mmol) and the reaction mixture was stirred at room temperature for24 hours. It was diluted with water (20 ml) and extracted with CH₂Cl₂(3×30 ml). The organic layer was washed with water (2×30 ml) and brine(30 ml), dried over Na₂SO₄, and evaporated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0%to 5%) to give (±) cis 123.

To a solution of (±) cis 123 in CH₂Cl₂ (5 ml) was added dropwise TFA (5ml) at 0° C. The mixture was stirred at 0° C. for 2 hours and thesolvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ (10ml), washed with saturated K₂CO₃ solution (5 ml), dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give (±) cis 124(0.225 g, 33%) as clear oil. ¹H NMR (CDCl₃) δ 1.38-1.43 (m, 1H),1.47-1.54 (m, 2H), 1.62-1.66 (m, 1H), 1.74-1.87 (m, 3H), 2.01-2.04 (m,1H), 2.29 (s, 3H), 2.71 (d, J=14 Hz, 1H), 2.76 (d, J=14 Hz, 1H), 3.25(s, 3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H), 7.29-7.38 (m, 2H), 7.59 (s, 1H).¹³C NMR (CDCl₃) δ 21.9, 23.7, 25.0, 31.6, 48.7, 49.1, 56.7, 68.1, 83.3,128.4, 129.5, 129.7, 131.1, 131.8, 145.8. ESI MS m/z 302.

B. Synthesis oftrans-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine(Trans 124)

The title compound was prepared from (±) trans 122 (0.91 g, 2.34 mmol)according to the procedure described above for the correspondingcis-isomer to give (±) trans 124 (0.219 g, 30%) as clear oil.

The enantiomers of (±) trans 124 were separated using preparative HPLC(ChiralPak OD column; hexanes:IPA:DEA=95:5:0.1; 8 ml/min; λ=280 nm) togive trans 124 E1 (retention time=10 min) and trans 124 E2 (retentiontime=18 min). The absolute configurations of the chiral centers were notdetermined. ¹H NMR (CDCl₃) δ 1.24-1.42 (m, 2H), 1.60-1.77 (m, 2H),1.85-1.92 (m, 2H), 2.33 (s, 3H), 2.70 (d, J=13.6 Hz, 1H), 2.93 (d,J=13.6 Hz, 1H), 3.33 (s, 3H), 3.64 (dd, J=7.6, 2.4 Hz, 1H), 7.25 (d,J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.47 (s, 1H). ¹³C NMR (CDCl₃) δ21.6, 21.8, 24.9, 30.6, 37.4, 46.8, 57.2, 58.5, 81.5, 127.2, 129.7,130.2, 130.4, 132.7, 145.1. ESI MS m/z 302.

1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N,N-dimethylmethanamine(125)

The following compounds were prepared from the respective monomethylamine according to General Procedure F. The crude products were purifiedby silica gel column chromatography (dichloromethane/methanol, 0-5%MeOH) to give the desired dimethyl amine.

(±) cis 125 was prepared from (±) cis 124 (54 mg, 83%, clear oil). ¹HNMR (CDCl₃) δ 1.35-1.42 (m, 2H), 1.47-1.54 (m, 2H), 1.62-1.66 (m, 1H),1.74-1.87 (m, 2H), 2.01-2.04 (m, 1H), 2.12 (s, 6H), 2.31 (d, J=14 Hz,1H), 2.65 (d, J=14 Hz, 1H), 3.31 (s, 3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H),7.32 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.70 (s, 1H). ¹³CNMR (CDCl₃) δ 21.9, 23.7, 25.0, 31.6, 48.7, 49.1, 56.7, 68.1, 83.3,128.4, 129.5, 129.7, 131.1, 131.8, 145.8. ESI MS m/z 316.

Trans 125 E1 and trans 125 E2 were prepared from trans 124 E1 and trans124 E2, respectively. 1H NMR (CDCl3) δ 1.24-1.39 (m, 3H), 1.42-1.60 (m,2H), 1.77-1.88 (m, 2H), 1.91 (s, 6H), 2.25 (d, J=13.6 Hz, 1H), 2.71 (d,J=13.6 Hz, 1H), 3.36 (s, 3H), 3.76 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.36(d, J=8.4 Hz, 1H), 7.49 (s, 1H). 13C NMR (CDCl3) δ 20.9, 21.5, 23.7,28.8, 48.3, 56.5, 67.6, 79.4, 127.6, 129.8, 130.2, 130.4, 132.2, 145.6.ESI MS m/z 316.

2.3. Synthesis of 2-Aminomethyl-2-aryl-cyclohexanol Analogs viaCarboxylic Acids

2.3.1. Preparation of Arylhydroxyacids (130a-130i)

The preparation of Arylhydroxyacids is outlined in Scheme 27, below.Commercial arylboronic acids 126 were converted to the arylleadintermediates 127 using lead acetate and mercuric acetate. Compounds 127were used in situ to α-arylate 2-ethylcyclohexanonecarboxylate toprovide ketoesters 128 as racemic mixtures in 32-71% overall yield.Reduction of racemic ketones 128 with sodium borohydride produced fourisomeric hydroxyester products, 129 (±) cis and 129 (±) trans in 29% toquantitative yields. The pair of cis isomers were separated from thepair of trans isomers to give the enantiomeric mixtures 129 (±) cis and129 (±) trans using a Biotage chromatography system (SorbentTechnologies, 800 g, 40-75 μm SiO₂, heptane/ether). Each of 129 (±) cisand 129 (±) trans were saponified with sodium hydroxide inmethanol/water to provide the hydroxyacids 130 (±) cis and 130 (±)trans, respectively, in 55% to quantitative yield after extraction.

2.3.2. General Procedure N Synthesis of Aryl-Plumbanetriyl Triacetate

A mixture of chloroform (e.g., 200 mL), lead (IV) acetate (e.g., 58.1 g,131 mmol, 1 eq), and mercuric acetate (2.09 g, 6.55 mmol, 0.05 eq) waswarmed to 40° C. The respective arylboronic acid (e.g., 131 mmol) wasadded in portions over 15 minutes. The mixture was stirred at 40° C. forone hour, then cooled to room temperature and stirred overnight. Thiscrude mixture was used immediately in the next reaction step.

The following compounds were prepared from the corresponding boronicacids 126 following the procedure outlined in General Procedure N,above:

-   (127a) (3,4-Dichlorophenyl)plumbanetriyl triacetate-   (127b) (3,4-Methylenedioxy)plumbanetriyl triacetate-   (127c) (4-Chlorophenyl)plumbanetriyl triacetate-   (127d) (3-Chlorophenyl)plumbanetriyl triacetate-   (127e) (4-Methoxyphenyl)plumbanetriyl triacetate-   (127f) (4-Chloro-3-fluorophenyl)plumbanetriyl triacetate-   (127g) (4-Trifluoromethylphenyl)plumbanetriyl triacetate-   (127h) (4-Trifluoromethoxyphenyl)plumbanetriyl triacetate-   (127i) Naphthalen-2-ylplumbanetriyl triacetate

2.3.3 General Procedure Q Synthesis of Esters (128a-128i)

To the crude reaction mixture of the respective lead intermediatearylplumbanetriyl triacetate 2 was slowly added pyridine (e.g., 31.8 mL,393 mmol) and ethyl-2-oxocyclohexanecarboxylate (e.g., 22.3 g, 131mmol). The reaction mixture was heated to 40° C. and stirred for 72hours and was then diluted with chloroform (e.g., 200 mL) and pouredinto water (e.g., 300 mL). The phases were separated and the organiclayer was washed with 2 N H₂SO₄ (2×200 mL), dried over MgSO₄, filtered,and concentrated. The residue was purified by silica gel flashchromatography using the indicated solvent systems to give the alph-ketoesters 3.

The following compounds were prepared from the correspondingintermediate 127 following the procedure outlined in General ProcedureQ, above:

-   (128a) (±) Ethyl-1-(3,4-Dichlorophenyl)-2-oxocyclohexane-carboxylate    (hexane/ethyl acetate, 100:0 to 90:10, 46%, white solid)-   (128b) (±) Ethyl-1-(3,4-methylenedioxy)-2-oxocyclohexane-carboxylate    (hexane/ethyl acetate, 9:1, 45%, white solid)-   (128c) (±) Ethyl-1-(4-Chlorophenyl)-2-oxocyclohexanecarboxylate    (hexane/diethyl ether, 96.6 g, 68%, light yellow oil)-   (128d) (±) Ethyl-1-(3-chlorophenyl)-2-oxocyclohexane-carboxylate    (hexane/diethyl ether, 130 g, 71%, white solid)-   (128e) (±) Ethyl-1-(4-methoxyphenyl)-2-oxocyclohexane-carboxylate    (hexane/ethyl acetate, 100:0 to 90:10, 87.0 g, 63%, yellow    semi-solid)-   (128f) (±)    Ethyl-1-(4-Chloro-3-fluorophenyl)-2-oxocyclohexane-carboxylate    (hexane/ethyl acetate, 100:0 to 95:5, 67.4 g, 52%, white solid).-   (128g) (±)    Ethyl-1-(4-Trifluoromethylphenyl)-2-oxocyclohexanecarboxylate    (hexane/ethyl acetate, 100:0 to 90:10, 43.0 g, 34%, white solid).-   (128h) Ethyl-1-(4-trifluoromethoxy)-2-oxocyclohexanecarboxylate    (hexane/diethyl ether, 49.5 g, 61%, colorless oil)-   (128i) (±) Ethyl-1-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate    (hexane/ethyl acetate, 100:0 to 90:10, 79.8 g, 60%, yellow    semi-solid)

2.3.4. NaBH₄ Reduction and Separation of Diastereomers (Synthesis of129a-129i)

General Procedure R:

To a solution of the respective ketoester 3 (e.g., 17.8 g, 56.5 mmol) inethanol (e.g., 280 mL) at 0° C. was added sodium borohydride (e.g., 2.56g, 67.8 mmol) portionwise. The mixture was stirred for 3 hours and wasthen concentrated. The residue was dissolved in diethyl ether (e.g., 200mL) and 2 N HCl (e.g., 125 mL) was then slowly added. The phases wereseparated and the aqueous layer was extracted with diethyl ether (e.g.,3×100 mL). The organic layers were combined and washed with brine (e.g.,125 mL), dried over MgSO₄, filtered, and concentrated. The crude productwas purified by silica gel flash chromatography using hexane/ethylacetate or hexane/ethyl ether gradients to give a mixture of cis/transdiastereomers (13-100 g, 59-96% yield).

Separation of the diastereomers was accomplished using a Biotagechromatography system (Sorbent Technologies, 800 g, 40-75 μm SiO₂,heptane/ether, 80:20 isocratic), unless otherwise indicated. Up to 20 gof crude product were separated per injection to obtain the finalproducts with 63-85% overall recovery. Generally, the mixture oftrans-enantiomers, (±) trans 129, eluted from the column first, followedby the mixture of cis-enantiomers, (±) cis 129.

The following compounds (cis- and trans-diastereomers each) wereprepared from the corresponding intermediate 128 following the procedureoutlined in General Procedure R, above.

-   (cis 129a) (±) cis    ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate-   (trans 129a) (±) trans    ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate-   (cis 129b) (±) cis    ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate-   (trans 129b) (±) trans    ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate-   (cis 129c) (±) cis    ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexane-carboxylate-   (trans 129c) (±) trans    ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexanecarboxylate-   (cis 129d) (±) cis    ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate-   (trans 4d) (±) trans    ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate

Separation of the diastereomers was accomplished on a Symmetry C18Column (50×250, 7μ; MeCN/water 55:45)

-   (cis 129e) (±) cis    ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate-   (trans 129e) (±) trans    ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate    The mixture of cis/trans isomers was separated by reverse-phase    chromatography.-   (cis 129f) (±) cis    ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate-   (trans 129f) (±) trans    ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate-   (cis 129g) (±) cis    ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate-   (trans 129g) (±) trans    ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate-   (cis 129h) (±) cis    ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate-   (trans 129h) (±) trans    ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate-   (cis 129i) (±) cis    ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate-   (trans 129i) (±) trans    ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate

2.3.5. Saponification (Synthesis of 130a-130i)

General Procedure S:

To a solution of the respective (±) cis- or trans-hydroxy ester 129(e.g., 3.90 g, 12.3 mmol) in water (e.g., 12.0 mL) and methanol (e.g.,22.0 mL) at 0° C. was slowly added sodium hydroxide (e.g., 1.18 g, 29.5mmol). The mixture was stirred overnight and was then carefullyacidified with 2 N HCl and extracted with ethyl acetate (3×50 mL). Theorganic layers were combined, washed with brine (e.g., 40 mL), driedover MgSO₄, and filtered. The solvent was removed in vacuo to give therespective carboxylic acid, either (±) trans 130 or (±) cis 130. Yieldsfor this conversion were found to be between 55% and quantitative.

The following compounds were prepared from the correspondingintermediate 129 following the procedure outlined in General ProcedureS, above.

-   (cis 130a) (±)    cis-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexane-carboxylic acid-   (trans 130a) (±)    trans-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexanecarboxylic acid-   (cis 130b) (±)    cis-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid-   (trans 130b) (±)    trans-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid-   (cis 130c) (±)    cis-1-(4-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid-   (trans 130c) (±)    trans-1-(4-Chlorophenyl)-2-hydroxycyclohexanecarboxylic acid-   (cis 130d) (±)    cis-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid-   (trans 130d) (±)    trans-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid-   (cis 130e) (±)    cis-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid-   (trans 130e) (±)    trans-2-Hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid-   (cis 130f) (±)    cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic acid-   (trans 130f)    (±)trans-1-(4-chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic    acid-   (cis 130g) (±)    cis-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylic acid-   (trans 130g) (±)    trans-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexane-carboxylic    Acid-   (cis 130h) (±)    cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylic acid-   (trans 130h) (±)    trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexane-carboxylic    acid-   (cis 130i) (±)    cis-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid-   (trans 130i) (±)    trans-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid    Preparation of 2-Phenylaminoalcohols (132a-132i)

PyBOP-mediated coupling of hydroxyacids (±) cis 130 and (±) trans 130with methylamine (e.g., General Procedure G) gave hydroxyamides (±) cis131 and (±) trans 131, respectively, in 39% to quantitative yield.Reduction of (±) cis 131 and (±) trans 131 with borane•dimethylsulfidecomplex gave aminoalcohols (±) cis 132 and (±) trans 132, respectively,in 39-95% yield. The enantiomers of (±) cis 132 and (±) trans 132 wereseparated using preparative chiral HPLC to give the fast movingenantiomer E1 and the slow moving enantiomer E2 (Scheme 28). Theabsolute configuration of the chiral centers was not determined.

2.3.6. General Procedure G2 (Amide Bond Formation)

A mixture of the respective carboxylic acid 130 (e.g., 3.56 g, 12.3mmol), PyBOP (e.g., 7.04 g, 13.5 mmol), methylamine (e.g., 2 M in THF,37.0 mL, 74.0 mmol), and triethylamine (e.g., 1.24 g, 12.3 mmol) wasstirred at room temperature overnight. The mixture was acidified with 2N HCl and was then extracted with ethyl acetate (e.g., 3×60 mL). Theorganic layers were combined, optionally washed with NaHCO₃ solution,washed with brine (e.g., 50 mL), dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica gel flashchromatography using hexane/ethyl acetate or CH₂Cl₂/MeOH gradientsand/or optionally triturated with e.g., diethyl ether to give therespective N-methyl amine 131.

2.3.7. General Procedure G3 (Amide Bond Formation)

A mixture of respective carboxylic acid 130 (e.g., 9.50 g, 37.3 mmol),PyBOP (e.g., 19.4 g, 37.3 mmol), methylamine (e.g., 2 M in THF, 20.5 mL,41.0 mmol), N-methylmorpholine (e.g., 4.50 mL, 41.0 mmol) and DMAP(e.g., 5.00 g, 41.0 mmol) was stirred in DMF (e.g., 373 mL) at roomtemperature overnight. The mixture was diluted with EtOAc (e.g., 3 L).The layers were separated and the organic layer was washed with 0.5 MHCl (e.g., 3×1 L), saturated aqueous NaHCO₃ (3×600 mL), saturatedaqueous LiCl (600 mL), brine (600 mL), dried, filtered and concentrated.The residue was purified by silica gel chromatography using hexane/ethylacetate or CH₂Cl₂/MeOH gradients to give the respective N-methyl amine131.

The following compounds were prepared from the correspondingintermediate 130 using the procedures outlined in General Procedure G2or General Procedure G3, above, or slightly modified versions thereof

-   (cis 131a) (±)    cis-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexane-carboxamide-   (trans 131a) (±)    trans-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide-   (cis 131b) (±)    cis-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide-   (trans 131b) (±)    trans-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide-   (cis 131c) (±)    cis-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide-   (trans 131c) (±)    trans-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide-   (cis 131d) (±)    cis-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide-   (trans 131d) (±)    trans-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide-   (cis 131e) (±) cis    2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexanecarboxamide-   (trans 131e) (±) trans    2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexane carboxamide-   (cis 131f) (±)    cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane    carboxamide-   (trans 131f) (±)    trans-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane    Carboxamide-   (cis 131g) (±)    cis-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane    Carboxamide-   (trans 131g) (±)    trans-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane    Carboxamide-   (cis 131h) (±)    cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane    Carboxamide-   (trans 131h) (±)    trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane    Carboxamide

2.3.8. General Procedure T (Reduction of Amide 131 to Amine 132)

To a solution of the respective N-methylcarboxamide 131 (e.g., 2.70 g,8.93 mmol) in tetrahydrofuran (90.0 mL) was slowly addedborane•dimethylsulfide (2 M in THF, 13.4 mL, 26.8 mmol). The mixture wasstirred 48 hours at reflux. After cooling, the mixture was acidified bycareful addition of 2 N HCl. The mixture was concentrated in vacuo andthe residue was washed with diethyl ether (e.g., 60 mL). The phases wereseparated and the aqueous layer was made basic through addition of 2 NNaOH and was then extracted with ethyl acetate (e.g., 3×150 mL). Theethyl acetate layers were combined, washed with brine (100 mL), driedover MgSO₄, filtered, and concentrated. The residue was purified bysilica gel flash chromatography using e.g., dichloromethane/methanolgradients to give the respective amines (±) cis 132 and (±) trans 132.

The enantiomers for each of the amines (±) cis 132 and (±) trans 132were separated using preparative chiral HPLC. Typical conditions arelisted below:

1. ChiralPak AD; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm.2. Regis O1; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm.Absolute configurations of the chiral centers were not determined.Compounds are identified by E1 for the fast moving enantiomer and E2 forthe slow moving enantiomer.

The following compounds were prepared from the correspondingintermediate 131 using the procedures outlined in General Procedure T ora slightly modified version thereof.

cis-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclohexanol (133)

The enantiomeric mixture of (±) cis 132a was separated (ChiralPak ADcolumn; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 133 E1(retention time=15.5 min) and 133 E2 (retention time=20.7 min). ¹H NMR(CDCl₃) δ 0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H),1.78-1.84 (m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz,1H), 2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40 (d,J=8.4 Hz, 1H), 7.71 (dd, J=12.0, 2.4 Hz, 1H), 7.96 (s, 1H). ¹³C NMR(CDCl₃) δ 21.3, 24.9, 29.9, 35.9, 36.7, 46.2, 66.9, 81.4, 118.0, 129.2,130.4, 131.6, 132.6, 142.7. ESI MS m/z 289.

trans-2-(3,4-Dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (134)

The enantiomeric mixture of (±) trans 132a was separated (ChiralPak ADcolumn; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; and λ=275 nm) to give134 E1 (retention time=13.4 min) and 134 E2 (retention time=18.9 min).¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m,1H), 2.32 (s, 3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H),4.20 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.69 (d, J=1.6 Hz,1H). ¹³C NMR (CDCl₃) δ 21.9, 24.3, 32.4, 36.7, 37.5, 45.7, 57.1, 74.1,126.7, 129.4, 130.4, 130.6, 132.9, 146.5. ESI MS m/z 289.

cis-2-(4-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (135)

The enantiomeric mixture (±) cis 132c can be separated (e.g., Regis O1column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give135 E1 and 135 E2.

trans-2-(4-chlorophenyl)-2-((methylamino)methyl)-cyclohexanol (136)

The enantiomeric mixture (±) trans 132c was separated (Regis O1 column;hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give 136 E1(retention time=6.8 min) and 136 E2 (retention time=8.9 min). ¹H NMR(CDCl₃) δ 1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31(s, 3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.24 (dd,J=10.0 Hz, 3.2 Hz, 1H), 7.30 (d, J=10.8 Hz, 2H), 7.58 (d, J=10.8 Hz,2H). ¹³C NMR (CDCl₃) δ 21.9, 24.4, 32.4, 36.7, 37.5, 45.7, 57.1, 74.3,128.6, 128.9, 132.1, 144.6. ESI MS m/z 254.

cis-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (137)

The enantiomeric mixture of (±) cis 132d can be separated (e.g., RegisO1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give137 E1 and 137 E2.

trans-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (138)

The enantiomeric mixture (±) trans 132d was separated (Regis O1 column;hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give 138 E1(retention time=5.9 min) and 138 E2 (retention time=7.6 min). ¹H NMR(CDCl₃) δ 1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31(s, 3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.25 (dd,J=10.0 Hz, 3.2 Hz, 1H), 7.18-7.22 (m, 1H), 7.29-7.32 (m, 1H), 7.48-7.52(m, 1H), 7.60 (s, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.4, 32.5, 36.7, 37.5,45.9, 57.2, 74.1, 125.3, 126.7, 127.4, 134.8, 148.3. ESI MS m/z 254.

cis-2-((methylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (139)

The enantiomeric mixture (±) cis 132e was separated (Regis O1 column;hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=275 nm) to give 139 E1(retention time=5.7 min) and 139 E2 (retention time=7.1 min). ¹H NMR(CDCl₃) δ 1.02-1.10 (m, 1H), 1.21-1.39 (m, 3H), 1.62-1.66 (m, 1H),1.76-1.94 (m, 2H), 2.04-2.08 (m, 1H), 2.26 (s, 3H), 2.62 (d, J=12.4 Hz,1H), 2.88 (d, J=12.4 Hz, 1H), 3.77 (s, 3H), 3.96 (dd, J=11.2 Hz, 4.0 Hz,1H), 6.86 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H). ¹³C NMR (CDCl₃) δ21.4, 25.0, 30.0, 35.8, 36.7, 46.2, 55.3, 67.1, 81.9, 113.8, 130.4,133.7, 157.8. ESI MS m/z 250.

(±) trans-2-(4-Methoxyphenyl)-2-((methylamino)methyl)cyclohexanol (140)

The enantiomeric mixture (±) trans 132e was separated (ChiralPak ADcolumn; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=275 nm) to give140 E1 (retention time=5.3 min) and 140 E2 (retention time=7.1 min). ¹HNMR (CDCl₃) δ 1.23-1.46 (m, 4H), 1.62-1.87 (m, 3H), 1.92-2.00 (m, 1H),2.28 (s, 3H), 2.95 (d, J=12.4 Hz, 1H), 3.24 (d, J=12.4 Hz, 1H), 3.78 (s,3H), 4.25 (dd, J=10.4 Hz, 3.2 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 7.48 (d,J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.1, 24.4, 32.5, 36.7, 37.7, 45.1,55.4, 57.6, 74.4, 114.1, 128.0, 137.9, 157.9. ESI MS m/z 250.

cis-2-(4-Chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol(141)

The enantiomeric mixture (±) cis 132f was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 141 E1(retention time=7.2 min) and 141 E2 (retention time=10.8 min). ¹H NMR(CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 2.32(s, 3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.19 (dd,J=10.0 Hz, 3.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.42-7.52 (m, 1H). ¹³C NMR(CDCl₃) δ 22.0, 24.4, 32.5, 36.8, 37.7, 45.7, 57.1, 74.3, 115.7, 115.9,118.6, 118.7, 123.6, 130.7, 147.5, 157.2, 159.7. ESI MS m/z 272.

trans-2-(4-chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol(142)

The enantiomeric mixture (±) trans 132f was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 142 E1(retention time=6.7 min) and 142 E2 (retention time=8.6 min). ¹H NMR(CDCl₃) δ 0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H),1.78-1.84 (m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz,1H), 2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.34 (d,J=8.4 Hz, 1H), 7.56 (dd, J=12.0, 2.4 Hz, 1H), 7.74 (dd, J=12.0, 2.4 Hz,1H). ¹³C NMR (CDCl₃) δ 21.3, 24.9, 29.9, 35.9, 36.7, 46.8, 67.0, 81.5,118.0, 118.3, 125.9, 126.0, 130.4, 143.4, 156.9, 159.3. ESI MS m/z 272.

cis-2-((methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol(143)

The enantiomeric mixture (±) cis 132g was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 143 E1(retention time=8.2 min) and 143 E2 (retention time=11.8 min). ¹H NMR(CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H),1.61-1.70 (m, 1H), 1.79-1.85 (m, 1H), 1.93-1.99 (m, 2H), 2.03 (s, 6H),2.67 (d, J=13.6 Hz, 1H), 3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0 Hz,3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 1.2 Hz, 2H). ¹³CNMR (CDCl₃) δ 22.0, 24.4, 32.5, 36.8, 37.7, 46.0, 57.1, 74.2, 123.1,125.6, 125.7, 125.9, 127.5, 128.5, 128.8, 150.3. ESI MS m/z 288.

trans-2-((Methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol(144)

The enantiomeric mixture (±) trans 132g was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 144 E1(retention time=7.9 min) and 144 E2 (retention time=11.2 min). ¹H NMR(CDCl₃) δ 0.91-1.02 (m, 1H), 1.27-1.43 (m, 3H), 1.65-1.69 (m, 1H),1.83-1.88 (m, 2H), 2.11-2.16 (m, 1H), 2.28 (s, 3H), 2.68 (d, J=13.6 Hz,1H), 2.97 (d, J=13.6 Hz, 1H), 4.02 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d,J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.4, 24.9,30.0, 36.0, 36.7, 47.1, 67.1, 81.6, 125.3, 125.4, 125.8, 128.3, 128.6,129.9, 146.6. ESI MS m/z 288.

cis-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol(145)

The enantiomeric mixture (±) cis 132h was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 145 E1(retention time=5.1 min) and 145 E2 (retention time=8.2 min). ¹H NMR(CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H),1.30-1.48 (m, 4H), 1.68-1.88 (m, 3H), 1.99-2.03 (m, 1H), 2.32 (s, 3H),3.02 (d, J=12.4 Hz, 1H), 3.31 (d, J=12.4 Hz, 1H), 4.27 (dd, J=10.4 Hz,4.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). ¹³C NMR(CDCl₃) δ 21.3, 22.0, 24.5, 32.5, 36.7, 37.9, 45.5, 57.1, 74.3, 119.4,120.8, 121.1, 122.0, 128.5, 131.0, 144.7, 147.6. ESI MS m/z 304.

trans-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol(146)

The enantiomeric mixture (±) trans 132h was separated (Regis O1 column;hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 146 E1(retention time=4.4 min) and 146 E2 (retention time=5.8 min). ¹H NMR(CDCl₃) δ 0.96-1.04 (m, 1H), 1.25-1.42 (m, 3H), 1.65-1.69 (m, 1H),1.81-1.88 (m, 2H), 2.07-2.16 (m, 1H), 2.29 (s, 3H), 2.68 (d, J=11.6 Hz,1H), 2.95 (d, J=11.6 Hz, 1H), 4.00 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.18 (d,J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.3, 25.0,30.0, 36.0, 36.7, 46.6, 67.1, 81.6, 119.4, 120.8, 122.0, 131.0, 140.7,147.5. ESI MS m/z 304.

cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (147)

The enantiomeric mixture of (±) cis 132i was separated (ChiralPak ADcolumn; hexanes:IPA:DEA=90:10:0.1; μ=60 ml/min; λ=280 nm) to give 147 E1(retention time=20.7 min) and 147 E2 (retention time=28.2 min). ¹H NMR(CDCl₃) δ 0.96-1.03 (m, 1H), 1.22-1.41 (m, 3H), 1.60-1.65 (m, 1H),1.84-1.92 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (s, 3H), 2.66 (d, J=13.6 Hz,1H), 3.01 (d, J=13.6 Hz, 1H), 4.05 (dd, J=10.0 Hz, 3.2 Hz, 1H),7.19-7.24 (m, 2H), 7.71-7.87 (m, 4H), 8.49 (s, 1H). ¹³C NMR (CDCl₃) δ21.6, 25.1, 30.1, 35.9, 36.7, 47.1, 66.7, 81.9, 126.0, 126.1, 126.6,127.5, 128.3, 128.5, 129.5, 132.1, 133.6, 139.3. ESI MS m/z 270.

trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (148)

The enantiomeric mixture (±) trans 132i was separated (ChiralPak ADcolumn; hexanes:IPA:DEA=90:10:0.1; μ=60 ml/min; λ=280 nm) to give 148 E1(retention time=25.7 min) and 148 E2 (retention time=40.8 min). ¹H NMR(CDCl₃) δ 1.28-1.50 (m, 4H), 1.71-1.86 (m, 2H), 1.95-2.06 (m, 2H), 2.25(s, 3H), 3.06 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.45 (dd,J=10.0 Hz, 3.2 Hz, 1H), 7.39-7.44 (m, 2H), 7.60-7.63 (m, 1H), 7.76-7.85(m, 3H), 8.14 (s, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.6, 32.7, 36.8, 37.7,45.9, 57.1, 74.4, 124.8, 125.9, 126.2, 126.3, 127.5, 128.4, 128.5,132.2, 133.8, 143.2. ESI MS m/z 270.

cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (149)

(a) cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide(300)

A mixture of (±) cis-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylicacid (9.74 g, 36.1 mmol), PyBOP (18.8 g, 36.1 mmol), methylamine (2 M inTHF, 19.8 mL, 39.7 mmol), N-methylmorpholine (4.36 mL, 39.7 mmol) andDMAP (4.84 g, 39.7 mmol) was stirred in DMF (361 mL) at room temperatureovernight. The mixture was diluted with EtOAc (1.5 L). The layers wereseparated and the organic layer was washed with 0.5 M HCl (3×600 mL),saturated aqueous NaHCO₃ (3×500 mL), brine (300 mL), dried andconcentrated. The residue was triturated with diethyl ether to give (±)cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (7.36g, 72%) as a light yellow solid.

(b) cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol

The title compound can be prepared from the above amide, for example,according to General Procedure E.

(±) trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (150)

(a) (±)trans-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (301)

A mixture of (±)trans-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid (9.72 g,36.0 mmol), PyBOP (18.7 g, 36.0 mmol), methylamine (2 M in THF, 19.8 mL,39.6 mmol), N-methylmorpholine (4.35 mL, 39.6 mmol) and DMAP (4.83 g,39.6 mmol) was stirred in DMF (360 mL) at room temperature overnight.The mixture was diluted with EtOAc (1.5 L). The layers were separatedand the organic layer was washed with 1 M HCl (3×600 mL), saturatedaqueous NaHCO₃ (3×500 mL), brine (500 mL), dried and concentrated togive (±)-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide(8.66 g, 85%) as a light yellow solid.

(b) trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol

The title compound can be prepared from the above amide, for example,according to General Procedure E.

2.4. Preparation of Tertiary Amines (151a to 151i)

Treatment of the respective methylamines 132 (Scheme 29) with amethylating reagent, e.g., iodomethane and N,N′-diisopropylethylamine(DIEA) in acetone or CH₂Cl₂ (modified General Procedure F) gave thedimethylamines cis 151 E1, cis 151 E2, trans 151 E1, and trans 151 E2.

(Modified General Procedure F)

To the solution of the respective N-methylamine 132 (e.g., 86 mg, 0.285mmol) and DIEA (e.g., 0.164 ml, 0.942 mmol) in acetone (0.5 ml) wasadded CH₃I (e.g., 0.020 ml, 0.314 mmol). The mixture was stirred at roomtemperature overnight and the solvent was then removed in vacuo. Theresidue was dissolved in CH₂Cl₂ (e.g., 10 ml), washed with saturatedK₂CO₃ solution (e.g., 5 ml), dried over Na₂SO₄, and evaporated in vacuo.The crude product was purified by silica gel flash chromatography usinge.g., dichloromethane/methanol gradients to give the respectivedimethylamine 151 in 40 to 70% yield.

The following compounds were prepared from the corresponding methylamine133-148 using modified General Procedure F outlined above, or slightlymodified versions thereof.

cis-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (152)

152 E1, 152 E2

The title compounds were prepared from 133 E1 and 133 E2, respectively.¹H NMR (CDCl₃) δ 0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H), 1.28-1.39 (m,2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70(d, J=13.2 Hz, 1H), 3.97 (dd, J=11.2, 4.8 Hz, 1H), 7.37 (d, J=8.4 Hz,1H), 7.73 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.98 (d, J=2 Hz, 1H). ¹³C NMR(CDCl₃) δ 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8, 129.5, 130.0,130.2, 131.9, 132.4, 143.7. ESI MS m/z 303.

trans-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (153)

153 E1, 153 E2

The title compounds were prepared from 134 E1 and 134 E, respectively.¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m,1H), 1.77-1.98 (m, 3H), 2.03 (s, 6H), 2.58 (d, J=14.0 Hz, 1H), 3.25 (d,J=14.0 Hz, 1H), 4.18 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H),7.46 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H). ¹³C NMR (CDCl₃)δ 22.1, 24.1, 32.5, 36.9, 44.6, 44.7, 66.3, 74.8, 127.0, 129.6, 130.0,130.3, 132.5, 148.2. ESI MS m/z 303.

trans-2-(4-chlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (154)

154 E1, 154 E2

The title compounds were prepared from 136 E1 and 136 E2, respectively.¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m,1H), 1.77-1.84 (m, 1H), 1.89-1.98 (m, 2H), 2.03 (s, 6H), 2.58 (d, J=14.0Hz, 1H), 3.20 (d, J=14.0 Hz, 1H), 4.26 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.30(d, J=10.8 Hz, 2H), 7.58 (d, J=10.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.1,24.1, 32.5, 36.7, 44.6, 47.7, 66.3, 74.8, 128.6, 128.8, 131.8, 146.0.ESI MS m/z 268.

Cis-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (155)

155 E1, 155 E2

The title compounds were prepared from 139 E1 and 139 E2, respectively.¹H NMR (CDCl₃) δ 0.92-1.00 (m, 1H), 1.07-1.12 (m, 1H), 1.25-1.36 (m,2H), 1.61-1.66 (m, 1H), 1.80-2.03 (m, 9H), 2.59 (q, J=13.2 Hz, 2H), 3.95(dd, J=11.6 Hz, 4.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz,2H). ¹³C NMR (CDCl₃) δ 21.1, 25.3, 30.0, 37.1, 45.5, 47.7, 55.3, 76.0,81.5, 113.6, 130.7, 134.6, 157.6. ESI MS m/z 264.

trans-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (156)

156 E1, 156 E2

The title compounds were prepared from 140 E1 and 140 E2, respectively.¹H NMR (CDCl₃) δ 1.26-1.37 (m, 2H), 1.43-1.48 (m, 2H), 1.58-1.66 (m,1H), 1.76-1.82 (m, 1H), 1.88-2.00 (m, 2H), 2.05 (s, 6H), 2.61 (d, J=14.0Hz, 1H), 3.14 (d, J=14.0 Hz, 1H), 4.31 (dd, J=10.0 Hz, 3.2 Hz, 1H), 6.86(d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.2, 13.7,32.4, 36.1, 44.0, 47.7, 55.4, 67.4, 74.9, 113.7, 128.2, 139.1, 157.7.ESI MS m/z 263.

Cis-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol(157)

157 E1, 157 E2

The title compounds were prepared from 141 E1 and 141 E2, respectively.¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m,1H), 1.77-1.98 (m, 3H), 2.03 (s, 6H), 2.56 (d, J=14.0 Hz, 1H), 3.25 (d,J=14.0 Hz, 1H), 4.18 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.32-7.35 (m, 2H), 7.43(d, J=8.4 Hz, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.1, 32.5, 36.9, 44.6, 44.7,66.4, 74.9, 115.8, 116.1, 118.2, 118.4, 123.8, 130.3, 148.9, 157.0,159.5. ESI MS m/z 286.

Trans-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol(158)

158 E, 158 E2

The title compounds were synthesized from 142 E1 and 142 E2,respectively. ¹H NMR (CDCl₃) δ 0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H),1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 3.97 (dd, J=11.2, 4.8 Hz, 1H), 7.28(t, J=8.4 Hz, 1H), 7.55-7.58 (m, 1H), 7.75-7.79 (m, 1H). ¹³C NMR (CDCl₃)δ 21.0, 25.1, 29.9, 37.2, 46.1, 47.7, 75.9, 80.8, 118.3, 118.5, 126.3,130.2, 144.4, 156.8, 159.3. ESI MS m/z 286.

cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol(159)

159 E1, 159 E2

The title compounds were prepared from 143 E1 and 143 E2, respectively.¹H NMR (CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m,2H), 1.61-1.70 (m, 1H), 1.79-1.85 (m, 1H), 1.93-1.99 (m, 2H), 2.03 (s,6H), 2.67 (d, J=13.6 Hz, 1H), 3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0Hz, 3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H). ¹³C NMR(CDCl₃) δ 22.1, 24.0, 32.4, 36.8, 44.9, 66.4, 74.8, 123.2, 125.3, 125.4,125.9, 127.7, 128.2, 128.5, 151.7. ESI MS m/z 302.

trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol(160)

160 E1, 160 E2

The title compounds were prepared from 144 E1 and 144 E2, respectively.¹H NMR (CDCl₃) δ 0.82-0.93 (m, 1H), 1.14-1.21 (m, 1H), 1.30-1.40 (m,2H), 1.67-1.70 (m, 1H), 1.87-2.09 (m, 9H), 2.65-2.75 (m, 2H), 4.00-4.05(m, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃)δ 21.1, 25.2, 30.0, 37.4, 46.4, 47.6, 76.0, 81.0, 125.1, 125.2, 125.9,128.0, 128.4, 130.2, 131.8, 147.6. ESI MS m/z 302.

cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol(161)

161 E1, 161 E2

The title compounds were prepared from 145 E1 and 145 E2, respectively.¹H NMR (CDCl₃) δ 1.26-1.37 (m, 2H), 1.43-1.50 (m, 2H), 1.59-1.68 (m,1H), 1.78-1.84 (m, 1H), 1.92-1.97 (m, 2H), 2.03 (s, 6H), 2.61 (d, J=14.0Hz, 1H), 3.24 (d, J=14.0 Hz, 1H), 4.28 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.16(d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.2, 24.0,32.4, 36.7, 44.4, 47.7, 66.7, 74.9, 119.5, 120.8, 122.0, 128.7, 131.2,146.1, 147.4. ESI MS m/z 302.

trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol(162)

162 E1, 162 E2

The title compounds were prepared from 146 E1 and 146 E2, respectively.¹H NMR (CDCl₃) δ 0.90-0.97 (m, 1H), 1.12-1.19 (m, 1H), 1.29-1.39 (m,2H), 1.65-1.69 (m, 1H), 1.84-2.04 (m, 9H), 2.60 (d, J=14.0 Hz, 1H), 2.70(d, J=14.0 Hz, 1H), 4.00 (dd, J=11.6 Hz, 4.0 Hz, 1H), 7.14 (d, J=8.4 Hz,2H), 7.88 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.0, 25.2, 29.9, 37.3,46.0, 47.7, 76.1, 81.1, 120.6, 122.0, 131.2, 141.7, 147.4. ESI MS m/z318.

Cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (163)

163 E1, 163 E2

The title compounds were synthesized from 147 E1 and 147 E2,respectively. ¹H NMR (CDCl₃) δ 0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H),1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 4.05 (dd, J=11.2, 4.8 Hz, 1H), 7.37(d, J=8.4 Hz, 1H), 7.73 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.98 (d, J=2 Hz,1H). ¹³C NMR (CDCl₃) δ 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8,126.0, 126.1, 126.6, 127.5, 128.3, 128.5, 129.5, 132.1, 133.6, 139.3.ESI MS m/z 284.

trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (164)

164 E1, 164 E2

The title compounds were prepared from 148 E1 and 148 E2, respectively.¹H NMR (CDCl₃) δ 1.29-1.42 (m, 2H), 1.47-1.54 (m, 2H), 1.65-1.74 (m,1H), 1.80-1.86 (m, 1H), 1.97-2.10 (m, 3H), 2.03 (s, 6H), 2.72 (d, J=14.0Hz, 1H), 3.26 (d, J=14.0 Hz, 1H), 4.49 (dd, J=9.6 Hz, 2.8 Hz, 1H),7.41-7.48 (m, 2H), 7.61 d, J=8.8 Hz, 1H), 7.79-7.86 (m, 3H), 8.18 (s,1H). ¹³C NMR (CDCl₃) δ 22.3, 24.0, 32.5, 36.4, 44.8, 47.8, 66.6, 75.1,125.5, 125.8, 126.0, 126.2, 127.5, 127.8, 128.5, 132.1, 133.8, 144.6.ESI MS m/z 284.

2.5. Preparation of4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine

A solution of the respective methylamine 132 (e.g., 26.5 mg, 0.0919mmol) in formaldehyde (e.g., 37%, 2 ml) and formic acid (e.g., 96%, 2ml) was heated at 100° C. for 2 hours. After cooling to roomtemperature, the mixture was washed with hexanes (e.g., 3×4 ml). Theaqueous solution was then made basic with 5 N KOH solution to pH 12. Themixture was extracted with t-butyl methylether (e.g., 3×5 ml) and thecombined organic layers were dried over Na₂SO₄, and the solvent wasevaporated. The residue was purified by reverse phase HPLC (C-18 column,CH₃CN/water, CH₃CN from 5% to 100%) to give the respective oxazine.

Cis-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine(165)

165 E1 prepared from 133 E1165 E2 prepared from 133 E2

¹H NMR (CDCl₃) δ 0.97-1.17 (m, 1H), 1.23-1.45 (m, 3H), 1.72-1.90 (m,3H), 2.03 (s, 3H), 2.15 (d, J=12.8 Hz, 1H), 2.81 (d, J=12.4 Hz, 1H),3.32-3.43 (m, 1H), 3.72 (d, J=7.8 Hz, 1H), 4.57 (d, J=7.8 Hz, 1H),4.89-4.97 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.81 (s,1H). ¹³C NMR (CDCl3) δ 21.2, 26.0, 27.8, 35.6, 41.0, 42.8, 69.1, 85.1,88.7, 129.5, 129.9, 130.4, 131.8, 132.0, 144.6. ESI MS m/z 300.

Trans-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine(166)

166 E1 prepared from 134 E1166 E2 prepared from 134 E2

¹H NMR (CDCl₃) δ 1.25-1.41 (m, 2H), 1.48-1.79 (m, 4H), 1.88 (d, J=13.8Hz, 1H), 1.98 (d, J=11.4 Hz, 1H), 2.13 (s, 3H), 2.58-2.68 (m, 2H), 3.62(d, J=7.5 Hz, 1H), 4.00 (s, 1H), 4.55 (d, J=7.5 Hz, 1H), 7.20-7.27 (m,1H), 7.39-7.46 (m, 2H). ¹³C NMR (CDCl3) δ 20.3, 22.1, 27.0, 28.4, 40.4,41.5, 68.5, 77.4, 87.8, 126.5, 129.3, 130.4, 130.7, 133.0, 144.7. ESI MSm/z 300.

2.6. Synthesis of cis- andtrans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol (167) (a)Synthesis of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile

To ice-cold DMSO (100 mL) was added 60% NaH (1.0g, 2.3 eq) in portions.The cooling bath was removed and the solution was stirred at ambienttemperature for ten minutes. A solution of2-(3,4-dichlorophenyl)acetonitrile (2.0g, 10.75 mmol) in DMSO (50 mL)was added. The brown solution was stirred for 15 minutes beforecis-1,4-dichlorobutene (1.0 mL, 0.9 eq) was added. The reaction mixturewas stirred overnight and was then poured into water. The product wasextracted with DCM. The organic layer was washed with brine, evaporated,diluted with 50% ethyl acetate in hexanes, washed with water, andevaporated. The residual oil was separated on silica to give the nitrile(966 mg, 43%) as a pale-brown oil. GCMS R_(t)=10.8 min m/z=237 (M+). ¹HNMR (CDCl₃, δ): 7.51 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28(dd, J=2.3, 8.5 Hz, 1H), 5.79 (s, 2H), 3.27 (d, J=14.7 Hz, 2H), 2.87 (d,J=14.7 Hz, 2H). ¹³C NMR (CDCl₃, δ): 141.9, 133.2, 132.1, 131.0, 128.5,127.6, 125.0, 124.0, 48.4.

(b) Synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol

A mixture of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile (119 mg,0.500 mmol) and borane-THF (2 mL, 1M in THF, 2 eq) was heated at 65° C.for 2 hours. The reaction was cautiously quenched with ethanol (0.5 mL),sodium hydroxide (1 mL, 5M aqueous) and stirred for two hours. It wasthen extracted with MTBE and evaporated. The residue was purified byHPLC to give cis 167 and trans 167.

Cis 167:

LCMS R_(t)=4.7 min, m/z=260 (M+1). ¹H NMR (CDCl₃, δ): 7.39 (d, J=8.4 Hz,1H), 7.37 (d, J=2.2 Hz, 1H), 7.13 (dd, J=2.2, 8.4 Hz, 1H), 4.48 (m, 1H),3.21 (s, 1H), 2.68 (dd, J=13.0, 15.7 Hz, 2H), 2.32 (dd, J=6.4, 13.7 Hz,1H), 2.2-1.8 (m, 4H), 1.7 (m, 1H), 1.2 (bs, 2H). ¹³C NMR (CDCl₃, δ):147.9, 132.2, 130.1, 129.2, 126.6, 72.9, 52.6, 51.9, 45.4, 34.3, 33.0.

Trans 167:

LCMS R_(t)=5.7 min, m/z=260 (M+1). ¹H NMR (CDCl₃, δ): 7.37 (d, J=8.4 Hz,1H), 7.35 (d, J=2.3 Hz, 1H), 7.11 (dd, J=2.3, 8.4 Hz, 1H), 4.33 (m, 1H),2.86 (d, J=13.0 Hz, 1H), 2.74 (d, J=13.0 Hz, 1H), 2.5 (bs, 3H), 2.25(dd, J=6.0, 14.0 Hz, 1H), 2.2-1.7 (m, 5H). ¹³C NMR (CDCl₃, δ): 149.2,132.2, 130.1, 129.9, 128.8, 126.1, 72.6, 52.7, 52.1, 46.7, 36.2, 32.8.

1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine (168)

(a) Synthesis of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbaldehyde

To a −78° C. solution of the nitrile (238 mg, 1 mmol) in 5 mL toluenewas added dibal (2 mL, 2 eq) dropwise. After 45 minutes, the coldsolution was quenched with ethyl acetate (2 mL) and stirred at ambienttemperature for 30 minutes. The solution was diluted with ethyl acetateand washed with 3M HCl, water, and brine. The organic layer was driedwith sodium sulfate, filtered and evaporated. The crude product waspurified by silica gel column chromatography to give the aldehyde (161mg, 67%) as a clear oil. TLC R_(f) (25% EA/Hex)=0.13. GCMS R_(t)=7.7 minm/z=165 (M+). ¹H NMR (CDCl₃, δ): 5.89 (t, J=3.1 Hz, 2H), 3.09 (t, J=2.8Hz, 2H), 2.96 (s, 3H), 2.6 (m, 2H), 2.2 (m, 2H). ¹³C NMR (CDCl₃, δ):180.2, 127.7, 39.1, 24.9, 23.4.

(b) Synthesis of1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine (168)

To a solution of the aldehyde (100 mg, 0.4154 mmol) in methylamine (2.1mL, 2M in THF, 10 eq) was added acetic acid (104 ul, 5% of volume), andenough methanol to make a clear solution. The solution was stirred fortwo hours. To this was added sodium borohydride (40 mg, 3 eq) andstirring was continued for 30 minutes. The reaction was quenched withaqueous potassium carbonate and extracted with MTBE. The organic phasewas separated and the solvent removed in vacuo. The residue wasredissolved in MTBE and extracted with 3M HCl. The aqueous phase wasseparated, chilled in ice, and basicified with KOH. The aqueous phasewas then extracted with MTBE and the solvent removed in vacuo. Theresidue was diluted in DCM, filtered through aminopropyl cartridge. Thesolvent was again removed to give the title compound (75.1 mg, 71%) as aclear oil. LCMS R_(t) (SCM)=6.28 min; m/z=256 (M+1). ¹H NMR (CDCl₃, δ):7.36 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.10 (dd, J=2.2, 8.4 Hz,1H), 5.73 (s, 2H), 5.67 (m, 6H), 2.31 (s, 3H). ¹³C NMR (CDCl₃, δ, mult):148.6(0), 132.2(0), 130.1(1), 129.8(0), 129.2(1), 129.1(1), 126.5(1),63.1(2), 50.6(0), 43.2(2), 37.1(3).

2.7. Synthesis of 2-Hydroxymethyl Analogs

Synthesis of Aryl Lactones

General Procedure K:

To a solution of lactone (5 mmol) and Pd(dba)₂ (5 mol %) and toluene (6mL) which was stirring under nitrogen in a sealed vial, was addedtri-t-butylphosphine (1 M in toluene, 5 mol %), LiHMDS (1M in hexanes,1.2 eq), and the aryl bromide (1.5 eq). The solution was heated in themicrowave for fifteen minutes (max temp=140° C.). After cooling, themixture was diluted with hexane, washed with 3M HCl, and evaporated.

Alternatively, To a flame-dried 250 mL round bottom flask was addedPd(dba)₂ (1 mol %) and toluene. The vessel was purged with nitrogen andsealed before tri-t-butylphosphine (1M in toluene, 1.1 mol %) was addedvia syringe followed by the aryl bromide (51.27 mmol) as a solution intoluene (15 mL). LiHMDS (1 M in hexanes, 1.3 eq) was added and thesolution was stirred at ambient temperature for 15 min. The lactone (1.3eq) was added dropwise as a solution in toluene (20 mL). The mixture wasallowed to stir at ambient temperature overnight (16 h) and thenpartitioned between hexane and, in succession, 10% aqueous HCl, 10%aqueous K₂CO₃, and brine. The volatile components were removed in vacuoto give the crude arylated lactone.

(2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol (169)

169 E1, 169 E2 (a) Synthesis of racemic7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one

The title compound was prepared in 30% yield according to GeneralProcedure K as a pale-yellow oil. GCMS R_(t) (SCM)=13.0 min; m/z=284(M+). ¹H NMR (CDCl₃, δ): 7.50 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H),7.25 (dd, J=2.3, 8.5 Hz, 1H), 4.05 (dd, J=4.9, 8.9 Hz, 1H), 3.94 (dd,J=2.4, 8.9 Hz, 1H), 2.8 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m,6H). ¹³C NMR (CDCl₃, δ, mult): 177.7(0), 140.7(0), 133.0(0), 131.7(0),130.7(1), 128.6(1), 125.9(1), 70.1(2), 51.7(1), 40.5(2), 34.0(2),26.9(2), 23.0(2), 22.9(2).

(b) (2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol

The title compound was prepared from racemic7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one and ethylamineaccording to General Procedures AA, followed by General Procedure E. Theracemic aminol was separated using a chiral column (Chiracel OD column;95:5:0.1 hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast movingenantiomer 169 E1 (R_(t)=7.5 min) and the slow moving enantiomer 169 E2(R_(t)=9.7 min). LCMS R_(t)=7.88 min, m/z=316 (M+1). ¹H NMR (CDCl₃, δ):7.4 (m, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.10 (d, J=12.3Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.6 (m, 2H), 2.3 (m, 1H), 1.9-1.3 (m,8H), 1.04 (t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃, δ, mult): 146.5(0),133.1(0), 130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 53.6 (br, 2),45.4(0), 43.9(2), 41.9(1), 39.8 (br, 2), 26.1(2), 24.8(2), 22.0(2),14.5(3).

cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclohexyl)methanol(170)

170 E1, 170 E2

The title compound was prepared from racemic7a-(3,4-dichlorophenyl)-hexahydroisobenzofuran-1(3H)-one and methylamineaccording to General Procedures AA and E. The racemic aminol wasseparated using a chiral column (Chiracel OD column; 95:5:0.1hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast moving enantiomer170 E1 (R_(t)=9.0 min) and the slow moving enantiomer 170 E2 (R_(t)=11.5min). LCMS R_(t)=6.46 min, m/z=302 (M+1). ¹H NMR (CDCl₃, δ): 7.42-7.40(m, 2H), 7.18 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.05 (d, J=12.3 Hz,1H), 2.67 (d, J=12.3 Hz, 1H), 2.35 (s, 3H), 2.0-1.2 (m, 9H). ¹³C NMR(CDCl₃, δ, mult): 146.4(0), 133.0(0), 130.8(1), 130.0(0), 128.5(1),125.7(1), 63.2(2), 62.5(2), 45.4(2), 42.4 (0), 41.8(1), 36.0(3),26.1(2), 24.8(2), 22.0(2).

cis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol (171)

171 E1, 171 E2 (a) Synthesis of 7a-Phenyl-hexahydro-isobenzofuran-1-one

The title compound was prepared from hexahydro-isobenzofuran-1-one (10g,1.3 eq) and phenyl bromide (5.4 mL, 51.27 mmol) according to GeneralProcedure K. It was obtained as a clear oil (7.40g, 67%). HPLC R_(t)(5-100-8)=9.8 min. ¹H NMR (CDCl₃, δ): 7.4-7.2 (m, 5H), 4.05 (dd, 1H),3.90 (dd, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H).¹³C NMR (CDCl₃, δ, mult): 178.6 (0), 140.5 (0), 128.8 (1), 127.3 (1),126.3 (1), 70.3 (2), 52.5 (0), 41.0 (1), 34.2 (2), 27.5 (2), 23.4 (2),23.2 (2).

(b) Synthesis of 2-Hydroxymethyl-1-phenyl-cyclohexanecarboxylic aciddimethylamide

The amide was synthesized from the above lactone according to GeneralProcedure AA. The crude product was purified by silica gel columnchromatography to give a clear oil (239 mg, 100%). ¹H NMR (CDCl₃, δ):7.4-7.0 (m, 5H), 5.4 (bs, 1H), 3.5-3.2 (m, 4H), 3.0 (m, 1H), 2.6 (m,1H), 2.4 (m, 1H), 2.2 (m, 1H), 2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.3 (m,3H), 1.17 (t, 3H), 0.90 (t, 3H). ¹³C NMR (CDCl₃, δ, mult): 175.5 (0),142.9 (0), 128.7 (br), 126.8 (1), 63.1 (2), 57.3 (0), 53.3 (1), 43.1(2), 41.1 (2), 35.2 (2), 26.7 (2), 26.6 (2), 23.4 (2), 13.0 (3), 12.1(3).

(c) Synthesis ofcis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol

The title compound was synthesized from the above amide according toGeneral Procedure E. The enantiomeric amines were separated on aChiracel OD semiprep column (95:5:0.05 Hex/IPA/DEA) to give thefast-moving enantiomer 171 E1 (6.6 mg, 5.4%) and the slow-movingenantiomer 171 E2 (6.0 mg, 4.9%). LCMS R_(t)=5.84 min, m/z=248 (M+1). ¹HNMR (CDCl₃, δ): 7.42 (d, J=7.7 Hz, 2H), 7.31 (t, J=7.8 Hz, 2H), 7.18 (t,J=7.3 Hz, 1H), 3.95 (dd, J=6.6, 11.5 Hz, 1H), 3.83 (d, J=11.5 Hz, 1H),2.96 (d, J=13.5 Hz, 1H), 2.6 (m, 1H), 2.53 (d, J=13.5 Hz, 1H), 1.99 (s,6H), 1.9-1.1 (m, 8H). ¹³C NMR (CDCl₃, δ): 128.0, 127.0, 125.6, 64.2,46.6, 45.3, 41.6, 26.8, 24.2, 22.1.

cis-(2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexyl)methanol(172)

172 E, 172 E2

Powdered LAH (76 mg, 4 eq) was added to a solution of1-(3,4-dichlorophenyl)-2-(hydroxymethyl)-N,N-dimethylcyclohexanecarboxamide(0.5 mmol) in THF (5 mL). After one hour at ambient temperature, thereaction was quenched with aqueous ammonium chloride, washed with MTBE,basicified with KOH, extracted with MTBE and evaporated to give thecrude amine (108 mg) as a yellow-black oil. The crude oil was filtered(aminopropyl) and the enantiomers were separated on a Chiracel OD column(98:2:0.1 Hex/IPA/DEA) to give the fast-moving enantiomer 172 E1 (30.1mg, 19%) and the slow-moving enantiomer 172 E2 (26.6 mg, 17%). LCMSR_(t)=8.33 min, m/z=316 (M+1). ¹H NMR (CDCl₃, δ): 7.50 (d, J=2.4 Hz,1H), 7.38 (d, J=8.6 Hz, 1H), 7.26 (dd, J=2.4, 8.6 Hz, 1H), 3.92 (dd,J=6.5, 11.6 Hz, 1H), 3.77 (dd, J=1.2, 11.7 Hz, 1H), 2.95 (d, J=13.7 Hz,1H), 2.5 (m, 2H), 2.02 (s, 6H), 1.8-1.1 (m, 8H). ¹³C NMR (CDCl₃, δ,mult): 147.6, 132.2, 129.9, 129.6, 129.3, 126.6, 63.9, 46.8, 45.4, 41.8,38.7, 29.7, 26.5, 23.9, 22.0.

cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol(173)

rac 173, 173 E1, 173 E2 (a) Synthesis ofcis-6a-(3,4-dichlorophenyl)hexahydro-1H-cyclopenta[c]furan-1-one

The title compound was prepared from lactone (630 mg, 5 mmol) anddichlorophenylbromide (1.69g, 1.5 eq) according to General Procedure K.The crude product was separated by silica gel column chromatography togive the lactone (578 mg, 44%) as a pale-brown oil. TLC R_(f) (25%EA/hex)=0.34. GC-MS R_(t)=12.48 min, m/z=270 (M+). ¹H NMR (CDCl₃, δ):7.49 (d, J=2.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.3, 8.4 Hz,1H), 4.50 (dd, J=7.3, 9.6 Hz, 1H), 4.14 (dd, J=2.2, 9.6 Hz, 1H), 3.1 (m,1H), 2.60 (ddd, J=3.0, 6.4, 12.5 Hz, 1H), 2.2-1.6 (m, 5H). ¹³C NMR(CDCl₃, δ, mult): 179.7(0), 140.6(0), 132.8(0), 131.5(0), 130.6(1),128.3(1), 125.8(1), 72.7(2), 59.4(0), 46.2(1), 40.3(2), 34.4(2),25.8(2).

(b) Synthesis ofcis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol

The title compound was prepared from the above lactone and methylamineaccording to General Procedures AA and E to give racemic 173, which wasseparated by chiral HPLC (AD column; 2:3:95:0.1 MeOH:EtOH:Hex:DEA) togive the fast moving enantiomer 173 E1 (6.5 min) and the slow movingenantiomer 173 E2 (8.5 min). LCMS (14 min) R_(t)=5.98 min, m/z=288(M+1). ¹H NMR (CDCl₃, δ): 7.6 (m, 1H), 7.4 (m, 2H), 6.8 (bs, 1H), 3.7(m, 2H), 2.8 (m, 3H), 2.32 (s, 3H), 2.1-1.2 (m, 6H). ¹³C NMR (CDCl₃, δ,mult): 147.3(0), 132.5(0), 130.2(1), 130.1(1), 129.3(0), 126.9(1),63.7(2), 58.3(2), 52.9(0), 47.1(1), 41.6(2), 36.0(3), 28.6(2), 22.1(2).

2.8. Synthesis of 2-Methyl-Cycloalkylamines(±)-cis-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methanaminehydrochloride (174)

The title compound was synthesized from1-(3,4-dichlorophenyl)-2-methylcyclohexanecarbonitrile (159 mg, 0.60mmol) according to General Procedure E, followed by HCl salt formation.The crude HCl salt was recrystallized from CH₃CN (1.5 mL) to give thetitle compound as white crystals. HPLC R_(t)=8.86 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.60-7.59 (m, 1H), 7.58-7.50 (m, 1H), 7.39-7.35 (m, 1H),3.32-3.13 (m, 2H), 2.13-2.04 (m, 1H), 1.73-1.33 (m, 8H), 0.86 (d, J=6.96Hz, 3H); LC-MS 8.8 min, (M+1)⁺ 272 @ 9.0 min.

(±)cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmethanaminehydrochloride (175)

((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamine freebase (110 mg, 0.41 mmol), paraformaldehyde (ca. 100 mg), polymer boundcyanoborohydride (762 mg, 2.13 mmol/g, 1.62 mmol) and concentrated AcOH(1 mL) were suspended in 10 mL THF. The solution was shaken overnight,then filtered and diluted with EtOAc. The organic phase was washed with3M NaOH (2×20 mL) and brine (20 mL), dried (Na₂SO₄), filtered andconcentrated. The crude material was dissolved in Et₂O (3 mL) and HCl(ca. 1.5 mL, 2.0 M in Et₂O) was added. A white ppt. formed immediately.The crude HCl salt was recrystallized from EtOAc (1.5 mL) to give pure((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmethanaminehydrochloride as white crystals. HPLC R_(t)=9.1 min; ¹H NMR (400 mHz,MeOH-d⁴) 7.73 (d, J=2.2 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.51-7.48 (m,1H), 3.58-3.54 (m, 1H), 3.42-3.39 (m, 1H), 2.64-2.52 (m, 6H), 2.20-2.18(m, 2H), 1.83-1.76 (m, 1H), 1.63-1.42 (m, 6H), 1.01 (d, J=7.33 Hz, 3H);LC-MS 10.1 min, (M+1)⁺ 300 @ 10.3 min.

(±)cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanamine(176)

((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamine freebase (421 mg, 1.55 mmol) was dissolved in 3:1 THF:H₂O (8 mL) and K₂CO₃(322 mg, 2.33 mmol) was added. The solution was stirred for 2 minutes,then BOC₂O (338 mg, 1.55 mmol) was added. After 2 h, the solution waspoured into H₂O and the layers were separated. The organic layer waswashed with H₂O (1×20 mL) and brine (1×20 mL), dried (Na₂SO₄), filteredand concentrated. A portion of the N—BOC amine (113 mg) was useddirectly in the next reaction. LAH (34 mg, 0.9 mmol) was suspended inanhydrous THF (2 mL) and the amine (113 mg, 0.30 mmol) in anhydrous THF(3 mL) was added dropwise. The solution was heated in the MW (160° C., 5min, FHT). The crude reaction was quenched with 6M HCl (10 mL). Thesolution was washed with EtOAc (2×20 mL) and the EtOAc washes werediscarded. After the pH of the aqueous phase was adjusted to 12 with 3MNaOH, it was washed again with EtOAc (3×20 mL). The combined “second”organic washes were dried (Na₂SO₄), filtered and concentrated. The crudeamine was purified by PTLC with 10% MeOH/CH₂Cl₂ to give((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanamineas a clear oil. HPLC R_(t)=8.91 min; ¹H NMR (400 mHz, CDCl₃) 7.48 (d,J=2.57 Hz, 1H), 7.39-7.36 (m, 1H), 7.25-7.23 (m, 1H), 2.71 (s, 2H), 2.38(s, 3H), 2.11-2.03 (m, 1H), 1.85-1.73 (m, 2H), 1.70-1.60 (m, 1H),1.53-1.33 (m, 5H), 0.83 (d, J=6.98 Hz, 3H); LC-MS 8.70 min, (M+1)⁺ 286 @8.97 min.

(±) cis-N-((1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methyl)ethanamine(177)

t-Butyl (1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methylcarbamate (97mg, 0.261 mmol) was dissolved in anhydrous DMF (3 mL) and NaH (60%dispersion in mineral oil, 21 mg, 0.52 mmol) was added. The solution washeated via MW (75° C., 5 min), and cooled to RT. Ethyl iodide (62 mL,0.78 mmol) was added and the solution was heated via MW (100° C., 20min). The yellow mixture was poured into H₂O (20 mL) and washed withEt₂O (3×20 mL). The combined organic washes were dried (Na₂SO₄),filtered and concentrated. Purification by silica gel columnchromatography with 0→10% EtOAc/hexanes gave tert-butyl(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32 mg,0.08 mmol) as a clear oil. tert-butyl(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32 mg,0.08 mmol) was dissolved in 1:1 CH₂Cl₂:TFA (3 mL) and stirred for 2 hthen concentrated. The crude amine was dissolved in EtOAc (20 mL) andwashed with 3M NaOH (2×20 mL) and brine (20 mL), then dried (Na₂SO₄),filtered and concentrated. The crude amine was purified by PTLC with 10%MeOH/CH₂Cl₂ to give the title compound as a clear oil. HPLC R_(t)=9.17min; ¹H NMR (400 mHz, CDCl₃) 7.51 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz,1H), 7.27-7.25 (m, 1H), 2.76 (d, J=1.47 Hz, 2H), 2.59 (q, 2H), 2.08-2.05(m, 1H), 1.78-1.77 (m, 1H), 1.67-1.64 (m, 1H), 1.52-1.36 (m, 5H), 1.05(at, 3H), 0.81 (d, J=6.97 Hz, 3H); LC-MS 8.94 min, (M+1)⁺ 300 @ 9.17min.

Example 3 Synthesis of 3-Substituted Cyclohexylamine Analogs

3.1. Synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)-cyclohexanolanalogs

The synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol isoutlined in Scheme 30, below. Reaction of 3-ethoxy-2-cyclohexen-1-one178 with 3,4-dichlorophenylmagnesium bromide in THF followed byquenching the Grignard mixture with diluted H₂SO₄ gave3-(3,4-dichlorophenyl)-2-cyclonexen-1-one 179. Addition of CN⁻ to theα,β-unsaturated ketone by heating 179 with KCN in the presence of NH₄Clin aqueous DMF afforded the cyano ketone 180 in 30% yield. The ketonewas reduced to the alcohol 181 using NaBH₄ in ethanol at 0° C. The majorproduct was the cis diastereomer and the minor product was the transdiastereomer. The amine 182 was formed through reduction of the nitrilewith BH₃-THF at room temperature overnight in 83% yield. Protection ofthe amino group with Boc-anhydride afforded 183. The diastereomers werethen separated using reverse phase HPLC.

3.1.1. Preparation of Boc Protected Primary Amines 14

The primary amine 182 (mixture of cis and trans diastereomers, 1.8 g,6.57 mmol) was added to a 10% triethylamine solution in MeOH (40 ml). Tothis mixture was added di-tert-butyl dicarbonate (1.72 g, 7.88 mmol)with vigorous stirring. The mixture was stirred at room temperature for3 hours. The solvent was then removed in vacuo. The residue wasdissolved in EtOAc (70 ml), washed with saturated K₂CO₃ solution (3×40ml), 5% HCl (2×40 ml), brine (40 ml), dried over Na₂SO₄, and evaporated.The residue was purified by silica gel column chromatography(MeOH/CH₂Cl₂, MeOH from 0 to 5%) to yield 183 (2.45 g, 97%) as a clearoil. The diastereomers of 183 were separated (C-18 column, 50%acetonitrile, 50% water) to give the the cis isomer cis 183 (1.83g) andthe trans isomer trans 183 (0.45g).

Cis 183:

¹H NMR (CDCl₃) δ 1.19-1.31 (m, 4H), 1.37 (s, 9H), 1.68-1.72 (m, 1H),1.87-1.90 (m, 1H), 2.13 (d, J=12.8 Hz, 1H), 2.41 (d, J=12.8 Hz, 1H),2.58 (brs, 1H), 3.09-3.22 (m, 2H), 3.54-3.66 (m, 1H), 4.72 (t, J=6.0 Hz,1H), 7.18-7.21 (m, 1H), 7.40-7.49 (m, 2H). ¹³C NMR (CDCl3) δ 20.2, 28.5,32.7, 35.8, 42.0, 44.8, 53.5, 66.8, 79.7, 126.7, 129.4, 130.6, 130.8,133.0, 143.9, 156.3. ESI MS m/z 374.

Trans 183:

¹H NMR (CDCl₃) δ 1.21-1.38 (m, 4H), 1.39 (s, 9H), 1.60-1.66 (m, 1H),1.87-1.90 (m, 1H), 1.98 (d, J=10.8 Hz, 1H), 2.26 (d, J=10.8 Hz, 1H),2.76 (brs, 1H), 3.30-3.45 (m, 2H), 398-4.08 (m, 1H), 7.06-7.18 (m, 1H),7.39-7.43 (m, 2H). ¹³C NMR (CDCl₃) δ 20.4, 28.5, 33.0, 35.1, 42.1, 43.1,46.6, 67.1, 79.7, 125.6, 128.4, 130.5, 130.6, 132.8, 147.6, 156.2. ESIMS m/z 374.

3.1.2. Chiral HPLC Separation of Enantiomers

The enantiomers of cis 183 were separated using a preparative HPLCprocedure (ChiralPak OD column; hexanes:IPA=90:10; 8 ml/min; λ=280 nm)to give cis 183 E1 (retention time=10 min) and cis 183 E2 (retentiontime=18 min). The absolute configuration of the chiral centers was notdetermined.

The enantiomers of trans 183 were separated using a preparative HPLCprocedure (ChiralPak OD column; hexanes:IPA=90:10; 8 ml/min; λ=280 nm)to give trans 183 E1 (retention time=15 min) and trans 183 E2 (retentiontime=21 min). The absolute configuration of the chiral centers was notdetermined.

3.1.3. Preparation of Primary Amines 182 (Removal of Boc-Group)

General Procedure U:

To the solution of the respective Boc-protected primary amine 183 (e.g.,38 mg, 0.102 mmol) in CH₂Cl₂ (e.g., 2 ml) was added TFA (e.g., 2 ml) at0° C. The mixture was stirred at 0° C. for one hour and the solvent wasremoved in vacuo. The residue was dissolved in CH₂Cl₂ (10 ml), washedwith saturated K₂CO₃ solution (2×3 ml), dried over Na₂SO₄, and thenfiltered through an aminopropyl cartridge. The solvent was removed togive the respective primary amine 182.

The following compounds were prepared following the procedure outlinedin General Procedure U, above.

Cis-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (184)

184 E1, 184 E2

¹H NMR (CDCl₃): δ 1.21-1.39 (m, 4H), 1.42-1.52 (m, 2H), 1.63-1.70 (m,1H), 1.80-1.90 (m, 1H), 2.20 (d, J=12.8 Hz, 1H), 2.43 (d, J=12.8 Hz,1H), 2.62 (s, 2H), 3.51-3.60 (m, 1H), 7.16-7.20 (m, 1H), 7.40-7.49 (m,2H). ¹³C NMR (CDCl₃) δ 20.5, 32.8, 36.2, 42.5, 45.5, 57.0, 67.0, 126.9,129.5, 130.7, 130.8, 133.0, 144.3. ESI MS m/z 274.

Trans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (185)

185 E1, 185 E2

¹H NMR (CDCl₃): δ 1.21-1.30 (m, 4H), 1.42-1.58 (m, 3H), 1.77-1.82 (m,1H), 2.00-2.05 (m, 2H), 2.34-2.40 (m, 1H), 2.85 (d, J=13.2 Hz, 1H), 2.90(d, J=13.2 Hz, 1H), 3.85-3.93 (m, 1H), 7.18-7.20 (m, 1H), 7.40-7.43 (m,2H). ¹³C NMR (CDCl₃) δ 20.3, 32.6, 35.3, 42.2, 48.6, 67.4, 125.8, 128.6,130.4, 132.7, 133.9, 147.9. ESI MS m/z 274.

3.1.4. Preparation of Secondary Amines 15

General Procedure F1:

A solution of acetic anhydride (e.g., 0.118 ml, 1.254 mmol) and formicacid (e.g., 0.058 ml, 1.546 mmol) in THF (e.g., 1.5 ml) was heated in amicrowave at 100° C. for 5 min. After cooling to room temperature, asolution of the respective primary amine 182 (e.g., 107 mg, 0.392 mmol)in THF (e.g., 1.5 ml) was added. The mixture was heated in the microwaveat 100° C. for 5 min. The solvent was then removed in vacuo. The residuewas dissolved in THF (e.g., 1.5 ml), and BH₃-THF (e.g., 1 ml, 1.0 mmol)was added. The mixture was heated in the microwave at 60° C. for 6 min.The reaction was then quenched by the addition of MeOH (e.g., 2 ml) and6N HCl (e.g., 1 ml). The solvent was removed in vacuo. To the residuewas added 1 N NaOH solution to pH 12. The aqueous solution was extractedwith CH₂Cl₂ (e.g., 3×10 ml). The combined organic phases were dried overNa₂SO₄ and evaporated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/CH₂Cl₂, 0-10%) to give the respectivesecondary amine 186.

The following compounds were prepared according to the proceduresoutlined in General Procedure F1, above.

Cis-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (187)

187 E1, 187 E2

¹H NMR (CDCl₃): δ 1.37-1.42 (m, 1H), 1.49-1.58 (m, 1H), 1.63-1.70 (m,2H), 1.90-2.05 (m, 1H), 2.28 (d, J=12.8 Hz, 1H), 2.46 (s, 3H), 2.85 (d,J=12.4 Hz, 1H), 3.38 (d, J=12.4 Hz, 1H), 3.63-3.78 (m, 2H), 3.88-3.92(m, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.40-7.49 (m, 2H). ¹³C NMR (CDCl₃) δ20.3, 30.1, 33.7, 35.1, 45.5, 61.4, 62.9, 65.9, 126.3, 129.0, 131.2,131.4, 133.3, 144.1. ESI MS m/z 288.

Trans-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (188)

¹H NMR (CDCl₃): δ 1.15-1.26 (m, 1H), 1.36-1.44 (m, 2H), 1.52-1.63 (m,1H), 1.76-1.82 (m, 1H), 2.03 (t, J=13.2 Hz, 1H), 2.29 (s, 3H), 2.41-2.45(m, 1H), 2.68 (d, J=12.0 Hz, 1H), 2.78 (d, J=12.0 Hz, 1H), 3.84-3.91 (m,1H), 7.20 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.38-7.44 (m, 2H). ¹³C NMR (CDCl₃)δ 20.7, 33.9, 35.1, 37.4, 42.8, 42.9, 58.4, 67.0, 125.5, 128.3, 130.4,130.5, 132.7, 148.5. ESI MS m/z 288.

188 E1, 188 E2 3.1.5. Preparation of Tertiary Amines 189

General Procedure D1:

A mixture of 37% formaldehyde (e.g., 0.096 ml, 1.183 mmol) and 96%formic acid (e.g., 0.056 ml, 1.183 mmol) in water (e.g., 2 ml) was addedto the respective primary amine 182 (e.g., 130 mg, 0.473 mmol) at 0° C.The mixture was heated to 100° C. overnight. The reaction mixture wasthen washed with hexanes (e.g., 3×10 ml), and evaporated in vacuo. Theresidue was purified by reverse phase HPLC (C-18 column, CH₃CN/water,CH₃CN from 5% to 100%) to give the respective tertiary amine 189.

The following compounds were prepared according to General Procedure D1,above.

Cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (190)

190 E1, 190 E2

¹H NMR (CDCl₃): δ 1.23-1.36 (m 2H), 1.46-1.53 (m, 1H), 1.59 (dd, J=12.8Hz, 8 Hz, 1H), 1.68-1.73 (m, 1H), 1.81-1.85 (m, 1H), 2.05 (s, 6H),2.07-2.10 (m, 1H), 2.27 (d, J=13.6 Hz, 1H), 2.37 (d, J=13.6 Hz, 1H),2.43 (m, 1H), 2.63 (brs, 1H), 3.59-3.65 (m, 1H), 7.21 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H). ¹³C NMR (CDCl₃)δ 20.2, 33.7, 35.7, 42.2, 45.0, 48.4, 66.9, 73.5, 126.9, 129.4, 129.8,130.3, 132.5, 146.2. ESI MS m/z 302.

Trans-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (191)

191 E1, 191 E2

¹H NMR (CDCl₃) δ 1.16-1.26 (m, 1H), 1.34-1.45 (m, 2H), 1.50-1.61 (m,1H), 1.75-1.81 (m, 1H), 1.95 (s, 6H), 1.99-2.03 (m, 1H), 2.14 (brs, 1H),2.40-2.47 (m, 2H), 2.55 (d, J=13.6 Hz, 1H), 3.84-3.91 (m, 1H), 7.21 (dd,J=8.4 Hz, 2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H).13C NMR (CDCl₃) δ 20.6, 33.8, 35.1, 42.6, 43.0, 48.2, 66.3, 67.7, 125.8,128.5, 129.8, 130.0, 132.2, 150.0. ESI MS m/z 302.

3.1.6. Synthesis ofcis-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine (192)

To a solution of1-(3,4-dichloro-phenyl)-3-methoxy-cyclohexanecarbonitrile (150 mg, 0.53mmoL) in THF (5 mL) was added BH₃.THF (1.0 M, 1.59 mL, 1.59 mmoL). Thereaction mixture was stirred overnight before being concentrated. Theresidue was dissolved in MeOH (3 mL) and subjected to reverse phasecolumn chromatography (CH₃CN/H₂O/0.1% Formic acid=5% to 100%) to givethe desired product (109 mg, 72%).

3.2. Synthesis of 3-Disubstituted Aryl-Cyclohexylamines Synthesis of3-Aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (193)

The title compound was synthesized from1-(3,4-dichlorophenyl)-3-oxo-cyclohexanecarbonitrile (1.0 g, 3.7 mmol)according to General Procedure Y, followed by General Procedure E(Scheme 31). The crude product was dissolved in MeOH (4 ML) andsubjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formicacid=5% to 100%) to give (±)3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.57 g,81%).

193 E1, 193 E2

To a solution of3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.5 g, 1.74mmoL) in CH₂Cl₂ (15 mL) was added Et₃N (528 mg, 727 mL, 5.22 mmol) and(BOC)₂O (567 mg, 2.60 mmol). The reaction mixture was stirred for 2 h atroom temperature before being quenched by a saturated NH₄Cl solution(10.0 mL). The product was extracted with CH₂Cl₂ (2×15 mL). The combinedextracts were washed with saturated brine, dried and concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1:5) to afford (±)tert-butyl(1-(3,4-dichlorophenyl)-3-hydroxy-3-methylcyclohexyl)-methylcarbamate(0.61 g, 90%). The enantiomers were separated (chiral AD column withhexane/iso-propanol/DEA=95:5:0.1) to afford the fast moving enantiomerE1 (0.22 g, retention time 4.085 min) and the slow moving enantiomer E2(0.32 g, retention time 6.051 min). To a solution of the respectiveenantiomer E1 (200 mg, 0.52 mmol) or E2 (200 mg, 0.52 mmol) in CH₂Cl₂ (4mL) was added TFA (2.0 mL). The reaction mixtures were stirred for 0.5 hbefore being concentrated. The mixtures were each purified by reversephase column chromatography (CH₃CN/H₂O) to give the amines 193 E1 and193 E2 in each 80% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (broad, 1H),7.58 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.37 (dd, J=2.0, 8.4 Hz,1H), 3.55 (s, 2H), 2.15 (m, 2H) 1.88 (m, 1H), 1.74-1.58 (m, 4H), 1.40(m, 1H), 1.21 (m, 3H); ¹³CNMR (100 MHz, CD₃OD) δ 146.42, 132.75, 131.01,130.83, 128.41, 125.97, 69.31, 46.48, 44.85, 40.15, 37.81, 32.81, 32.54,30.91, 18.17; ESI MS m/z=288.4.

3.3. Synthesis of Chiral 3-Methoxy-Cyclohexylamines

1-(3,4-dichlorophenyl)-3-methoxycyclohexanecarbonitrile was synthesizedfrom 1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (1.5 g, 5.61mmoL) according to General Procedure W, followed by General Procedure EE(Scheme 32). The crude product was purified by silica gel columnchromatography (ethyl acetate/hexane=1:7).

The cis enantiomers (170 mg) were separated (chiral OD column;ethanol/methanol/hexane/DEA=1;1:98:0.1) to give the fast movingenantiomer E1 (67 mg) and the slow moving enantiomer E2 (81 mg).

E1 was converted to 192 and E2 (120 mg, 0.42 mmoL) was converted to 194according to General Procedure E. The crude product was dissolved inMeOH (3 mL) and subjected to reverse phase column chromatography(CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give the desired product(90.4 mg, 75%). ¹H NMR (400 MHz, CD₃Cl) δ 7.46 (m, 2H), 7.20 (m, 1H),3.02 (s, 3H), 3.08 (m, 1H), 2.83 (s, 2H), 2.46 (m, 1H), 2.22 (m, 1H),1.92 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H), 1.24 (m, 2H); ¹³C NMR (100MHz, CD₃Cl) δ 141.71, 133.41, 131.46, 131.27, 129.67, 126.84, 75.30,55.99, 51.80, 42.43, 39.20, 32.66, 31.31, 19.84; ESI MS m/z 288.1.

Likewise, the methylated trans-enantiomers (100 mg) were separated usinga chiral OD column (ethanol/methanol/hexane/DEA=1:1:98:0.1) to givetrans E1 (43 mg) and trans E2 (38 mg). Trans E2 (38 mg, 0.13 mmoL) wasconverted to the respective amine according to General Procedure E. Thecrude product was dissolved in MeOH (1 mL) and subjected to reversephase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) togive the desired product 195 E2 (31.2 mg, 82%). ¹H NMR (400 MHz, CD₃Cl)δ 7.47 (m, 2H), 7.22 (m, 1H), 3.04 (s, 3H), 3.10 (m, 1H), 2.85 (s, 2H),2.49 (m, 1H), 2.20 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.49 (m, 2H),1.26 (m, 2H); ¹³C NMR (100 MHz, CD₃Cl) δ 141.69, 133.52, 131.64, 131.09,129.78, 127.01, 76.01, 56.109, 51.68, 42.56, 39.40, 32.77, 31.42, 20.01;ESI MS m/z 288.1.

3.4. Synthesis of Secondary and Tertiary Amines

Compounds in Table 4, below were prepared from the indicated amineaccording to General Procedure F.

TABLE 4 R^(d) R^(e) R³ R⁴cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N- methylmethanamine(196) H OCH₃ CH₃ H The compound was prepared from 194. The crude productwas subjected to silica gel column chromatography (Ethylacetate/hexane/DEA = 1/4/0.1%) to give 196 (26.7 mg, 32%) and 197 (37.6mg, 37%). ¹H NMR (400 MHz, CD₃Cl) δ 7.43 (d, J = 2.0 Hz, 1 H), 7.41 (d,J = 8.8 Hz, 1 H), 7.21 (dd, J = 2.0, 8.8 Hz, 1 H), 3.12 (s, 3 H), 3.07(m, 1 H), 2.54 (m, 1 H), 2.55 (s, 2 H), 2.28 (s, 3 H), 2.26 (m, 1 H),2.19 (m, 1 H), 1.70 (m, 1 H), 1.40 (m, 2 H), 1.22 (m, 2 H); ¹³C NMR (100MHz, CD₃Cl) δ 144.77, 132.98, 130.68, 130.30, 129.44, 126.80, 75.83,66.66, 55.89, 44.22, 40.19, 37.53, 33.81, 33.37, 20.43; ESI MS m/z 308.1. cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-dimethylmethanamine (197) H OCH₃ CH₃ CH₃ The compound was prepared from194. The crude product was subjected to silica gel column chromatography(Ethyl acetate/hexane/DEA = 1/4/0.1%) to give 196 (26.7 mg, 32%) and 197(37.6 mg, 37%). ¹H NMR (400 MHz, CD₃Cl) δ 7.45 (d, J = 2.4 Hz, 1 H),7.38 (d, J = 8.4 Hz, 1 H), 7.22 (dd, J = 2.4, 8.4 Hz, 1 H), 3.22 (s, 3H), 3.06 (m, 1 H), 2.56 (m, 1 H), 2.28 (s, 2 H), 2.19 (m, 1 H), 2.02 (s,6 H), 2.04- 1.96 (m, 1 H), 1.68 (m, 1 H), 1.40 (m, 1 H), 1.20 (m, 2 H);¹³C NMR (100 MHz, CD₃Cl) δ 145.41, 132.53, 130.30, 129.84, 129.70,127.10, 75.99, 74.35, 55.88, 48.76, 45.54, 39.82, 33.19, 32.32, 20.46;ESI MS m/z 316 .1. cis-3-(3,4-dichlorophenyl)-1-methyl-3-((methylamino)methyl)cyclohexanol (198) CH₃ OH CH₃ H The compound wasprepared from 193 E2. ¹HNMR (400 MHz, CD₃OD) δ 7.51 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1 H), 7.31 (dd, J = 2.4, 8.4 Hz, 1 H), 3.31 (d,J = 13.2 Hz, 1 H), 3.20 (d, J = 13.2 Hz, 1 H), 2.23 (s, 3 H), 2.00 (m, 2H), 1.88 (m, 1 H), 1.75 (m, 1 H), 1.68 (m, 1 H), 1.60 (m, 2 H), 1.39 (m,1 H), 1.05 (s, 3 H); ¹³CNMR (100 m Hz, CD₃OD), δ 146.32, 132.08, 130.19,127.68, 128.37, 126.07, 69.45, 61.35, 46.74, 41.79, 38.58, 35.86, 32.74,30.36, 18.97; ESI MS m/z 302.1.cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-1-methylcyclohexanol (199) CH₃ OH CH₃ CH₃ The compound was prepared from193 E2. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (broad, 1 H), 7.64 (d, J = 2.0Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.42 (dd, J = 2.0, 8.8 Hz, 1 H),4.05 (d, J = 13.2 Hz, 1 H), 3.53 (d, J = 13.2 Hz, 1 H) 2.558 (s, 6 H),2.30 (m, 1 H), 2.15 (m, 1 H), 1.95 (m, 1 H), 1.80 (d, J = 14 Hz, 1 H),1.68 (m, 2 H), 1.41 (td, J = 4.0, 13.2 Hz, 2 H), 1.33 (s, 3 H); ¹³C NMR(100 MHz, CD₃OD) δ 148.30, 132.86, 130.99, 130.88, 128.21, 125.84,69.03, 65.32, 44.56, 41.65, 39.83, 37.63, 36.48, 30.89, 18.36; ESI MSm/z 316.2. cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-methylmethanamine (200) H OCH₃ CH₃ H The compound was prepared from 192.¹H NMR (400 MHz, CD₃Cl) δ 7.43 (d, J = 2.0 Hz, 1 H), 7.41 (d, J = 8.8Hz, 1 H), 7.21 (dd, J = 2.0, 8.8 Hz, 1 H), 3.12 (s, 3 H), 3.07 (m, 1 H),2.54 (m, 1 H), 2.55 (s, 2 H), 2.28 (s, 3 H), 2.26 (m, 1 H), 2.19 (m, 1H), 1.70 (m, 1 H), 1.40 (m, 2 H), 1.22 (m, 2 H); ¹³C NMR (100 MHz,CD₃Cl) δ 144.77, 132.98, 130.68, 130.30, 129.44, 126.80, 75.83, 66.66,55.89, 44.22, 40.19, 37.53, 33.81, 33.37, 20.43; ESI MS m/z 308.1.cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-dimethylmethanamine (201) H OCH₃ CH₃ CH₃ The compound was prepared from192. ¹H NMR (400 MHz, CD₃Cl) δ 7.45 (d, J = 2.4 Hz, 1 H), 7.38 (d, J =8.4 Hz, 1 H), 7.22 (dd, J = 2.4, 8.4 Hz, 1 H), 3.22 (s, 3 H), 3.06 (m, 1H), 2.56 (m, 1 H), 2.28 (s, 2 H), 2.19 (m, 1 H), 2.02 (s, 6 H), 2.04-1.96 (m, 1 H), 1.68 (m, 1 H), 1.40 (m, 1 H), 1.20 (m, 2 H); ¹³C NMR (100MHz, CD₃Cl) δ 145.41, 132.53, 130.30, 129.84, 129.70, 127.10, 75.99,74.35, 55.88, 48.76, 45.54, 39.82, 33.19, 32.32, 20.46; ESI MS m/z 316.1. cis-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (202)CH₃ OH CH₃ H The compound was prepared from 193 E1. ¹HNMR (400 MHz,CD₃OD) δ 7.51 (d, J = 2.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.31 (dd,J = 2.4, 8.4 Hz, 1 H), 3.31 (d, J = 13.2 Hz, 1 H), 3.20 (d, J = 13.2 Hz,1 H), 2.23 (s, 3 H), 2.00 (m, 2 H), 1.88 (m, 1 H), 1.75 (m, 1 H), 1.68(m, 1 H), 1.60 (m, 2 H), 1.39 (m, 1 H), 1.05 (s, 3 H); ¹³CNMR (100 m Hz,CD₃OD) δ 146.32, 132.08, 130.19, 127.68, 128.37, 126.07, 69.45, 61.35,46.74, 41.79, 38.58, 35.86, 32.74, 30.36, 18.97; ESI MS m/z 302.1.cis-3-(3,4-dichlorophenyl)-3- ((dimethylamino)methyl)cyclohexanol (203)CH₃ OH CH₃ CH₃ The compound was prepared from 193 E1. ¹H NMR (400 MHz,CD₃OD) δ 8.44 (broad, 1 H), 7.64 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 8.8Hz, 1 H), 7.42 (dd, J = 2.0, 8.8 Hz, 1 H), 4.05 (d, J = 13.2 Hz, 1 H),3.53 (d, J = 13.2 Hz, 1 H) 2.558 (s, 6 H), 2.30 (m, 1 H), 2.15 (m, 1 H),1.95 (m, 1 H), 1.80 (d, J = 14 Hz, 1 H), 1.68 (m, 2 H), 1.41 (td, J =4.0, 13.2 Hz, 2 H), 1.33 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 148.30,132.86, 130.99, 130.88, 128.21, 125.84, 69.03, 65.32, 44.56, 41.65,39.83, 37.63, 36.48, 30.89, 18.36; ESI MS m/z 316.2.

(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-methanamine (204)

The title compound was synthesized from1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (0.60 g, 2.2 mmol)according to General Procedure CC, followed by General Procedure E. Thecrude product was dissolved in MeOH (3 mL) and subjected to reversephase column chromatography (CH₃CN/H₂O/0.1% Formic acid=5% to 100%) togive (86 mg, 72%). ¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.4 Hz, 1H),7.57 (d, J=8.4 Hz, 1H), 7.39 (dd, J=2.4, 8.4 Hz, 1H), 3.23 (s, 2H), 2.4(m, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.80 (m, 2H); ¹³C NMR (100 MHz,CD₃OD) δ 142.17, 132.94, 131.58, 130.96, 129.06, 126.54, 123.11, 47.74,41.65, 40.23, 32.98, 30.69, 18.21, 41.26; ESI MS m/z 294.0.

1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N-methylmethanamine(205) 205 E1, 205 E2

The title compound was synthesized from 204 according to GeneralProcedure F. The crude product was subjected to silica gel columnchromatography (ethyl acetate/hexane/DEA=1:4:0.1) to give themono-methylated analog (25 mg, 30%) and the N, N-dimethylated analog (36mg, 41%). The racemic mixture of the monomethylated analog was purifiedby chiral column chromatography (OJ column;Hexane/^(i)propanol/DEA=98/2/0.1) to give the fast moving enantiomer 205E1 (5.2 mg) and the slow moving enantiomer 205 E2 (6.3 mg). ¹H NMR (400MHz, CD₃Cl) δ 7.42 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.18 (dd,J=2.4, 8.8 Hz, 1H), 2.68 (s, 2H), 2.38-2.19 (m, 2H), 2.29 (s, 3H),2.00-1.90 (m, 2H), 1.90-1.66 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 132.78,130.69, 130.45, 128.68, 126.09, 126.03, 123.69, 61.73, 45.5, 41.26,37.41, 34.14, 32.05, 18.84; ESI MS m/z 308.1.

1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N,N-dimethylmethanamine(206)

The racemic mixture of the dimethylated analog (Example above) waspurified by chiral column chromatography (OJ column;hexane:^(i)propanol:DEA=98:2:0.1) to give the fast moving enantiomer 206E1 (5.2 mg) and the slow moving enantiomer 206 E2 (6.3 mg). ¹H NMR (400MHz, CD₃OD) δ 7.41 (d, J=2.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.18 (dd,J=2.4, 8.8 Hz, 1H), 2.36 (s, 2H), 2.36-2.24 (m, 1H), 2.07 (s, 6H),1.94-1.80 (m, 4H), 1.74-1.64 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 136.17,132.27, 130.18, 129.99, 129.03, 126.47, 70.42, 48.52, 44.5, 40.26,34.12, 31.58, 18.881; ESI MS m/z 332.1.

Example 4 Synthesis of 4-Substituted Cyclohexylamine Analogs

4.1. Synthesis of Aryl Acetonitriles

General Procedure V:

To a 1.0 M solution of the carboxylic acid (1 eq) in THF was addedBH₃/THF (3 eq). The reaction mixture was stirred overnight before beingconcentrated. To the residue was added diethyl ether and NaOH solution.The organic layer was separated, dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to afford the aryl alcohol.

To a 0.4 M solution of the aryl alcohol (1 eq) in CH₂Cl₂ was added PBr₃(2 eq). The reaction mixture was stirred for 3 h at room temperaturebefore being quenched with saturated aqueous NH₄Cl. The organic layerwas separated, dried (Na₂SO₄) and concentrated. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to afford thearyl alkyl bromide.

To a 0.2M solution of the aryl alkyl bromide (1 eq) in CH₃CN was addedKCN (3 eq). The reaction mixture was heated to reflux for 6 h beforebeing concentrated. To the residue was added diethyl ether and H₂O. Theorganic layer was separated, dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to afford the desired aryl acetonitrile.

4.2. Synthesis of 1-(aryl)-4-oxocyclohexanecarbonitriles

Aryl-4-oxocyclohexanecarbonitriles were prepared according to theScheme, above, or procedures described in WO 00/25770 and WO 03/063797,the disclosures of which are incorporated herein by reference for allpurposes. Minor modifications of the described procedures were used whenappropriate. For example, 2.2 equivalents of acrylate may be used instep 1, NaH (60% dispersion in mineral oil) reduction was performed inrefluxing toluene, and microwave irradiation was used for reactions upto a multigram scale in the final decarboxylation step. An exemplarysynthesis of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile isoutlined below.

4.2.1. Synthesis of dimethyl 3-cyano-3-(naphthalen-2-yl)hexanedioate

2-naphthylacetonitrile (3.45 g, 20.6 mmol) and methyl acrylate (9.7 ml,107 mmol) were suspended in 2-methyl-2-propanol (10 ml). Heat wasapplied to the reaction vessel until the solution became clear. Themixture was cooled to room temperature, at which time (Bu)₄NOH (6.9mmol, 0.33 equiv.) was added as a solution in2-methyl-2-propanol:methanol (1:2). The combined reaction mixture washeated to reflux for 4 h under vigorous stirring at which time thereaction appeared complete by GC-MS. After allowing the reaction to coolthe mixture was partitioned between H₂O (75 ml) and EtOAc (50 ml). Theaqueous layer was removed and washed with EtOAc (2×50 ml). The combinedorganic phases were washed with NaHCO₃ (sat. aq.) and brine and driedover MgSO₄. After filtration the solvent was removed in vacuo. The crudeproduct was purified by flash column chromatography (25% EtOAc inhexanes) to isolate the title compound as a light yellow oil (5.75 g,82%).

4.2.2. Synthesis of methyl5-cyano-2-hydroxy-5-(naphthalen-2-yl)cyclohex-1-enecarboxylate

To a solution of the diester nitrile (2.3 g, 6.77 mmol) in dry toluene(46 ml) was added NaH (60% suspension in mineral oil, 820 mg, 20.33mmol). The reaction mixture was heated to reflux for 3 h at which timeno starting material remained (GC-MS). The reaction was cooled to roomtemperature and carefully quenched with NH₄Cl (aq., 100 ml) andextracted with EtOAc (3×50 ml). The combined organics were washed withbrine, dried over MgSO₄, filtered, and the solvent removed in vacuo. Theresulting oily product, suspended in mineral oil, was washed withhexanes to afford the desired product as a light yellow solid (1.4 g,67% yield). The material was used in the following step without furtherpurification.

4.2.3. Synthesis of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile

The above ketoester (0.75 g, 2.44 mmol) was dissolved in DMSO (11 ml)and H₂O (0.5 ml) and was sealed in a 20 ml microwave reaction vialequipped with a magnetic stir bar. The reaction mixture was heated to160° C. for 10 min in a microwave reactor at which time completeconversion was observed by HPLC. The reaction was diluted with EtOAc (50ml) and washed with 10% LiCl (aq., 2×30 ml) followed by a brine wash.The organic layer was removed, dried over MgSO₄, filtered, and thesolvent was removed in vacuo. The product was further purified by flashcolumn chromatography (25% EtOAc in hexanes) to afford the desiredketone (0.55 g, 90% yield) as a colorless oil, which solidified uponstanding.

4.3. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile (NaBH₄Reduction)

General Procedure W:

To a solution of the ketonitrile (1 eq) in dry methanol (about 0.1 M) at0° C. was added NaBH₄ (4 eq) portionwise. The mixture was allowed towarm to 22° C. and was stirred at this temperature for about 2 h, oruntil complete (e.g., HPLC). It was diluted with H₂O and the aqueouslayer was extracted with Et₂O. The combined organic layers were washedwith brine, dried over MgSO₄ and filtered. The solvent was removed invacuo to afford the resulting alcohol, typically as one diastereomer.

4.4. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile with InverseStereochemistry at C-4 (Mitsunobu Reaction)

General Procedure X:

To a solution of PPh₃ (1.2 eq) in dry toluene (about 0.1 M) was addedp-NO₂-benzoic acid (1.2 eq) and the resulting suspension was cooled to−30° C. To the mixture was added a 2 M solution of the respectivenitrile alcohol (1 eq) in toluene (about) in one portion and a 1.0 Msolution of DEAD (1.2 eq) in toluene dropwise over 15 min. The mixturewas allowed to warm to 22° C. and was stirred for 15 h, at which timethe reaction was quenched with saturated aqueous NaHCO₃. The aqueouslayer was extracted with EtOAc, the combined organic layers were driedover MgSO₄, filtered and the solvent was removed in vacuo to afford thebenzoate intermediate, which was used without further purification (0.61g, 74% yield).

To a solution of the crude benzoate (1 eq) in MeOH (about 0.1 M) wasadded a 1.0 M solution of NaOMe (95%, 1.11 eq) in THF and the mixturewas allowed to stir at 22° C. for 4 h. The solvent was removed in vacuoand the resulting residue was taken up in H₂O and extracted with EtOAc.The combined organics were dried over MgSO₄, filtered and the solventwas removed in vacuo. The crude product was purified by silica gelcolumn chromatography (EtOAc in hexanes) to afford the desired nitrilealcohol.

4.5. Synthesis of Tertiary Alcohols

General Procedure Y:

To a solution of the ketonitrile (1 eq) in dry THF (about 0.4 M) at −78°C. was added dropwise MeLi (1.4 M in Et₂O, 2 eq) so as to maintain aninternal temperature of <−60° C. The reaction mixture was stirred at−78° C. for 3 h and the reaction was then quenched with H₂O (e.g., 1ml). The reaction mixture was allowed to warm to 22° C. and was thendiluted with CH₂Cl₂. The organic layer was washed with aqueous NaHCO₃and brine, dried over MgSO₄ and filtered and the solvent was removed invacuo. The crude product was purified by flash column chromatography(e.g., 0-60% EtOAc in hexanes) to return starting material, fast movingdiastereomer as well as the slow moving diastereomer (major product).Solvent removal afforded the desired products as white solids.

4.6. Chlorination

General Procedure Z:

To a solution of the amino alcohol (1 eq) in MeOH containing 10% (v/v)NEt₃ was added BOC₂O (2 eq) and the resulting mixture was stirred at 22°C. for 3 h, at which time the solvent was removed in vacuo. Silica gelcolumn chromatography (e.g., EtOAc in hexanes) afforded the carbamate asa clear oil.

To a solution of the purified carbamate (1 eq) in DMF (about 0.1 M) andCCl₄ (1.5 eq) was added KF (3 eq) and PPh₃ (2 eq) and the resultingmixture was stirred at 22° C. for 3 h. Saturated aqueous NaHCO₃ was thenadded to quench the reaction and the aqueous layer was extracted withEtOAc. The combined organic phases were dried over Na₂SO₄, filtered andthe solvent was removed in vacuo to afford the halogenated mixture e.g.,as a 3:1 ratio of chlorinated to α-eliminated product (66% conversion).Silica gel column chromatography (e.g., EtOAc in hexanes) afforded thechlorinated carbamate.

The BOC group was removed and the HCl salt was prepared by the additionof 4M HCl (Et₂O) to the carbamate. After stirring for 1 h, the HCl saltwas filtered off.

4.7. Fluorination

General Procedure BB:

A 0.2 M solution of the nitrile alcohol (1 eq) in CHCl₃ was addeddrop-wise to a 0.1 M solution of morpholino sulfurtrifluoride (4 eq) inCHCl₃ (about 0.1 M) at −15° C. over 5 min. The resulting mixture wasstirred between −30 and −15° C. for 30 min, at which time MeOH (5 eq)and saturated aqueous NaHCO₃ were added. The aqueous layer was extractedwith EtOAc, dried over Na₂SO₄, filtered and the solvent removed invacuo. Silica gel column chromatography (e.g., EtOAc in hexanes)afforded fluorinated and α-eliminated products e.g., in a 1:1 ratio.

4.8. Difluorination

General Procedure CC:

A 0.5 M solution of the ketonitrile (1 eq) in CHCl₃ was added drop-wiseto a 2 M solution of morpholino sulfurtrifluoride (4 eq) in CHCl₃ at−30° C. over 5 min. The resulting mixture was stirred between −30 and 0°C. for 2 h, at which time MeOH and saturated aqueous NaHCO₃ were added.The aqueous layer was extracted with EtOAc, dried over Na₂SO₄, filteredand the solvent was removed in vacuo. Silica gel column chromatography(e.g., EtOAc in hexanes) afforded difluorinated and α-eliminatedproducts.

4.9. Synthesis of Fluoromethyl Analogs

General Procedure DD:

To a solution of the ketonitrile (concentration about 0.3 M, 1 eq) andtrimethylsulfonium iodide (1.5 eq) in dry DMSO was added a solution ofKOtBu (1.5 eq) in dry DMSO (about 0.7 M). The mixture was stirred at 22°C. for 5 h, at which time the reaction appeared complete by GC-MS. Thereaction mixture was diluted with brine, and extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered, and the solventwas removed in vacuo. The crude product was purified by silica gelchromatography (e.g., EtOAc in hexanes) to afford two diastereomericepoxides, termed the faster moving diastereomer (FMD) and the slowermoving diastereomer (SMD).

To a 1M solution of TBAF in THF (4 eq) in a clean glass reaction flaskwas added HF (48% in H₂O, 4 eq). The solvent was removed in vacuo andthe resulting mixture was added to a mixture of the above epoxide (1 eq)and KHF₂ (3 eq) in a microwave reaction vial. The reagents were washeddown the side of the vial with heptane (minimal volume) and the reactionmixture was heated in the microwave at 120° C., for 15 min (FHT). Afterthe reaction mixture was cooled to 22° C., the mixture was diluted withH₂O and saturated aqueous NaHCO₃ and was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered and the solventwas removed in vacuo to afford crude fluoromethylated nitrile, which waspurified by silica gel chromatography (EtOAc in hexanes) to afford thepure product as a white solid (>20:1 regioselectivity).

4.10. Synthesis of Methylamine

General Procedure F2:

To a 0.1 M solution of the amine (1 eq) in MeOH containing 10% (v/v)NEt₃ was added BOC₂O (1.2 eq) and the resulting mixture was stirred at22° C. for 3 h, at which time the solvent was removed in vacuo. Silicagel column chromatography (EtOAc in hexanes) afforded the carbamate.

To a 0.1 M solution of the purified carbamate (1 eq) in THF was addedLAH (1M THF, 2 eq) and the resulting mixture was heated to 65° C. for 6h. After the reaction was complete (HPLC), 6M HCl was added followed bysaturated aqueous K₂CO₃. The product was extracted with EtOAc. Thecombined organics were dried over MgSO₄, filtered and the solvent wasremoved in vacuo. The crude mono-methylamine was purified by eitherGilson RP-HPLC or by transformation to the HCl salt andrecrystallization.

4.11. Alkylation of Alcohol

General Procedure EE:

To a 0.2 M solution of the alcohol (1 eq) in THF was added NaH (60% inmineral oil, 1.5 eq). The reaction mixture was stirred for 20 min beforealkyl halide (2 eq) was added. It was stirred for 4 h before beingquenched with saturated NH₄Cl solution. The product was then extractedwith diethyl ether. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give O-alkylated product.

4.12. Preparation of Ketals

General Procedure FF:

To a 0.1 M solution of the ketone (1 eq) in benzene was added ethyleneglycol (3 eq) and TsOH—H₂O (0.4 eq). The reaction mixture was heated atreflux for 6 h before being concentrated. The residue was dissolved inEtOAc, washed with saturated aqueous NaHCO₃, dried (Na₂SO₄), filteredand concentrated. The residue was purified by silica gel columnchromatography (Ethyl acetate/hexane/DEA) to give the ketal.

4.13. Synthesis of 4-Substituted Cycloalkylamines

Compounds in Table 5, below, were synthesized from the respective1-(aryl)-4-oxocyclohexanecarbonitriles according to the indicatedGeneral Procedures.

TABLE 5 Summary of 4-Substituted Cycloalkylamines General Ar R^(b) R^(c)Procedure 4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (207)

H OH W, E HPLC R_(t) = 7.54 min; LC-MS (5 minute method) 2.24 min, (M +1)⁺ 256.0 @ 2.31 min; ¹H-NMR (400 MHz, CDCl₃) 7.84-7.75 (m, 4H),7.51-7.43 (m, 3H), 3.79 (m, 1H), 2.88 (brs, 2H), 2.10-1.97 (m, 4H),1.75-1.56 (m, 4H). 4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (208)

OH H W, X, E HPLC R_(t) = 6.83 min; LC-MS (15 minute method) 4.71 min,(M + 1)⁺ 256.0 @ 4.73 min; ¹H-NMR (400 MHz, CD₃OD) 8.04-7.93 (m, 4H),7.69-7.49 (m, 3H), 3.72 (m, 1H), 3.13 (s, 2H), 2.63 (d, J = 13.5 Hz,2H), 1.99-1.85 (m, 2H), 1.80-1.68 (m, 2H), 1.47-1.31 (m, 2H).4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (209)

OH Me Y, E HPLC R_(t) = 7.06 min; LC-MS (M + 1)⁺ 270.1; ¹H-NMR (400 MHz,CDCl₃) 7.86-7.79 (m, 4H), 7.58 (brs, 2H), 7.43-7.35 (m, 3H), 2.84 (brs,2H), 2.25 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H), 1.49 (m, 2H), 1.28 (s,3H). 4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (210)

Me OH Y, E HPLC R_(t) = 1.39; LC-MS (15 minute method) 6.92 min, (M +1)⁺ 270.0 @ 6.88 min.(4-chloro-1-(naphthalen-2-yl)cyclohexyl)methanamine (211)

Cl H W, E, Z HPLC R_(t) = 2.38 min; ¹H-NMR (400 MHz, CD₃OD) 8.07-7.95(m, 4H), 7.65 (dd, J = 9.0, 1.5 Hz, 1H), 7.61-7.51 (m, 2H), 4.14 (m,1H), 3.18 (s, 2H), 2.68 (d, J = 13.5 Hz, 2H), 2.20 (d, J = 13.5 Hz, 2H),1.89-1.62 (m, 4H). ¹³C-NMR (100 MHz, CD₃OD) 134.0, 132.9, 129.5, 128.1,127.4, 127.2, 126.4, 124.1, 58.6, 50.6, 40.4, 32.4, 32.1. LC-MS (15minute method) 8.10 min, (m/z) 274.0 @ 8.18 min.(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (212)

F H W, BB, E HPLC R_(t) = 2.14 min; ¹H-NMR (400 MHz, CD₃OD) 8.00-7.87(m, 4H), 7.63-7.51 (m, 3H), 4.76 (m, 0.5H), 4.61 (m, 0.5H), 3.19 (s,2H), 2.52 (m, 2H), 2.01-1.97 (m, 2H), 1.82-1.76 (m, 2H), 1.64-1.59 (m,2H). LC-MS (15 minute method) 7.30 min, (M + 1)⁺ 258.1 @ 7.36 min(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (213)

H F W, X, BB, E HPLC R_(t) = 1.48 min; ¹H-NMR (400 MHz, CDCl₃) 7.87-7.62(m, 4H), 7.52-7.44 (m, 3H), 4.75 (m, 0.5H), 4.63 (m, 0.5H), 2.79 (s,2H), 2.23 (d, J = 13.5 Hz, 2H), 1.97-1.90 (m, 4H), 1.70-1.52 (m, 2H).¹³C-NMR (100 MHz, CDCl₃) 128.6, 128.1, 127.6, 126.6, 126.3, 126.0,125.2, 90.6, 55.4, 28.1, 27.8, 27.6. LC-MS (M + 1)+ 258.1.4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)cyclohexanol (214)

H OH W, E HPLC R_(t) = 1.18 min; LC-MS (15 minute method) 4.51 min, (M +1)⁺ 250.0 @ 4.4.51 min; ¹H-NMR (400 MHz, CD₃OD) 8.38 (brs, 1H), 6.98 (d,J = 2.0 Hz, 1H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.82 (d, J = 8.0 Hz,1H), 5.95 (s, 2H), 3.78 (m, 1H), 3.03 (s, 2H), 2.04-1.91 (m, 4H),1.71-1.58 (m, 4H). ¹³C-NMR (100 MHz, CD₃OD) 120.3, 108.3, 107.1, 101.4,66.2, 63.5, 40.0, 29.0.4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol (215)

Me OH Y, E HPLC R_(t) = 1.64 min; ¹H-NMR (400 MHz, CD₃OD) 8.37 (brs,1H), 6.97 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),5.97 (s, 2H), 2.92 (s, 2H), 2.13 (d, J = 13.5 Hz, 2H), 1.89 (t, J = 13.0Hz, 2H), 1.56 (d, J = 13.5 Hz, 2H), 1.38 (t, J = 13.0 Hz, 2H), 1.05 (s,3H). ¹³C-NMR (100 MHz, CD₃OD) 120.8, 108.4, 107.4, 101.5, 34.1, 29.7,29.0, 28.8. LC-MS (M + 1)⁺ 264.1.4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol (216)

OH Me Y, E HPLC R_(t) = 2.03 min; LC-MS (15 minute method) 0.60 min,(M + 1)⁺ 264.1 @ 0.70 min; ¹H-NMR (400 MHz, CD₃OD) 8.44 (brs, 1H), 6.98(d, J = 1.5 Hz, 1H), 6.91 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5Hz, 1H), 5.96 (s, 2H), 3.11 (s, 2H), 2.20-2.01 (m, 2H), 1.77-1.71 (m,2H), 1.60-1.56 (m, 4H), 1.27 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD) 168.1,149.0, 147.0, 120.1, 108.3, 106.9, 101.4, 68.7, 39.7, 34.6, 30.0, 27.2.4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (217)

CH₂F OH DD, E HPLC R_(t) = 1.84 min; LC-MS (15 minute method) 6.65 min,(M + 1)⁺ 288.2 @ 6.75 min; ¹H-NMR (400 MHz, CD₃OD) 7.99-7.87 (m, 4H),7.63 (dd, J = 9.0, 2H), 7.54-7.50 (m, 2H), 4.04 (s, 1H), 3.92 (s, 1H),3.09 (s, 2H), 2.46 (d, J = 13.5 Hz, 2H), 2.03 (t, J = 13.5 Hz, 2H), 1.63(d, J = 13.5 Hz, 2H), 1.45 (t, J = 13.5 Hz, 2H). ¹³C-NMR (100 MHz,CD₃OD) 136.1, 133.9, 132.8, 129.3, 128.0, 127.4, 127.3, 126.3, 124.3,90.6, 88.9, 52.1, 41.0, 28.3, 28.2, 27.6.4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (218)

OH CH₂F DD, E HPLC R_(t) = 1.19 min; LC-MS (15 minute method) 4.91 min,(M + 1)⁺ 288.1 @ 4.89 min; ¹H-NMR (400 MHz, CD₃OD) 7.97-7.86 (m, 4H),7.63 (dd, J = 9.0, 2.0 Hz, 1H), 7.53-7.48 (m, 2H), 4.38 (s, 1H), 4.26(s, 1H), 3.35 (s, 2H), 2.33 (dt, J = 13.5, 3.5 Hz, 2H), 2.00 (m, 2H),1.81 (dt, J = 13.5, 3.5 Hz, 2H), 1.65 (m, 2H). ¹³C-NMR (100 MHz, CD₃OD)133.9, 132.9, 129.1, 128.1, 127.3, 126.3, 126.2, 125.9, 123.7, 89.4,87.7, 69.6, 45.9, 39.8, 28.5, 28.4.4-(aminomethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-cyclohexanol(219)

Me OH Y, E HPLC R_(t) = 1.45 min; LC-MS (15 minute method) 7.48 min,(M + 1)⁺ 304.1 @ 7.60 min; ¹H-NMR (400 MHz, CD₃OD) 8.40 (brs, 2H), 7.58(dd, J = 9.0, 2.5 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 3.00 (s, 2H), 2.20(d, J = 13.5 Hz, 2H), 1.96 (t, J = 13.5 Hz, 2H), 1.59 (d, J = 14.0 Hz,2H), 1.31 (t, J = 13.5 Hz, 2H), 1.07 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD)129.4, 121.5, 68.0, 51.9, 40.4, 34.0, 29.6, 28.5.4-(aminomethyl)-4-(4-(trifluoromethoxy)phenyl)cyclohexanol (220)

H OH W, E HPLC R_(t) = 1.34 min; ¹H-NMR (400 MHz, CDCl₃) 8.44 (brs, 1H),7.60- 7.56 (m, 2H), 7.33 (d, J = 9.0 Hz, 2H), 3.76 (m, 1H), 3.15 (s,2H), 2.11- 1.99 (m, 4H), 1.64 (m, 4H). ¹³C-NMR (100 MHz, CDCl₃) 168.0,148.4, 128.9, 121.4, 66.3, 49.0, 40.0, 29.0, 28.8. LC-MS (M + 1)⁺ 290.2.(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (221)

F F CC, E HPLC R_(t) = 1.18 min; LC-MS (15 minute method) 7.70 min, (M +1)⁺ 276.2 @ 7.76 min; ¹H-NMR (400 MHz, CD₃OD) 8.39 (brs, 2H), 8.01- 7.88(m, 4H), 7.64 (d, J = 8.5 Hz, 1H), 7.54-7.51 (m, 2H), 3.18 (s, 2H), 2.60(d, J = 13.5 Hz, 2H), 2.09-1.90 (m, 4H), 1.89-1.71 (m, 2H). ¹³C-NMR (100MHz, CD₃OD) 133.8, 132.9, 129.6, 128.1, 127.4, 127.0, 126.5, 126.4,123.8, 50.0, 30.2, 30.0, 29.7, 29.6.

Synthesis of Secondary and Tertiary Amines

Compounds in Table 6, below, were synthesized from the respective1-(aryl)-4-oxocyclohexanecarbonitriles according to the indicatedGeneral Procedures.

TABLE 6 Summary of Secondary and Tertiary Amines General Proce- Ar R¹ R³R⁴ R^(b) R^(c) dure1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-yl)- cyclohexanol (222)

H H CH₃ OH CH₃ F2 Prepared from: 209 ¹H-NMR (400 MHz, CDCl₃) 8.88 (brs,2H), 7.97-7.79 (m, 4H), 7.54- 7.46 (m, 3H), 3.12 (m, 2H), 2.24 (m, 2H),2.23 (t, J = 5.0 Hz, 3H), 2.04 (m, 2H), 1.71 (m, 2H), 1.60 (m, 2H), 1.35(s, 3H). ¹³C-NMR (100 MHz, CDCl₃) 133.7, 132.6, 129.6, 128.6, 127.6,127.0, 126.8, 126.7, 123.9, 70.1, 35.7, 35.1, 30.6. LC-MS (M + 1)⁺284.1. 1-methyl-4-((methylamino)methyl)-4-(naphthalen-2- yl)cyclohexanol(223)

H H CH₃ CH₃ OH E, F2 ¹H-NMR (400 MHz, CDCl₃) 9.24 (brs, 2H), 7.94-7.83(m, 4H), 7.57 (d, J = 9.0 Hz, 1H), 7.53-7.48 (m, 2H), 3.03 (s, 2H), 2.58(s, 3H), 2.59- 2.43 (m, 4H), 1.68 (d, J = 13.5 Hz, 2H), 1.46-1.39 (m,2H), 1.04 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) 137.8, 133.7, 132.5, 129.4,128.4, 127.7, 127.0, 126.7, 126.6, 124.5, 69.1, 62.4, 41.6, 35.1, 34.9,30.6, 28.2. LC-MS (M + 1)⁺ 284.1.4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2- yl)cyclohexanol(224)

H CH₃ CH₃ OH CH₃ C Prepared from: 209 ¹H-NMR (400 MHz, CDCl₃) 7.89-7.80(m, 4H), 7.60 (dd, J = 8.5, 2.0 Hz, 1H), 7.52-7.45 (m, 2H), 2.54 (s,2H), 2.35-2.21 (m, 2H), 2.00 (s, 6H), 1.99-1.85 (m, 2H), 1.73-1.53 (m,4H), 1.35 (s, 3H). LC-MS (M + 1)⁺ 298.0.4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2- yl)cyclohexanol(225)

H CH₃ CH₃ CH₃ OH C ¹H-NMR (400 MHz, CDCl₃) 7.93 (m, 4H), 7.68 (dd, J =8.8, 2.0 Hz, 1H), 7.52 (m, 2H), 3.42 (s, 2H), 2.50 (s, 6H), 2.44 (d, J =13.2 Hz, 2H), 2.05 (dt, J = 13.6, 3.2 Hz, 2H), 1.63 (d, J = 13.2 Hz,2H), 1.41 (dt, J = 13.6, 3.2 Hz, 2H), 1.05 (s, 3H). ¹³C-NMR (100 MHz,CDCl₃) 138.1, 135.3, 134.3, 130.9, 129.7, 129.3, 129.0, 128.2, 126.3,73.4, 69.5, 47.6, 42.8, 35.6, 31.4, 30.9. LC-MS (M + 1)⁺ 298.0.4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (226)

H H CH₃ H OH F2 Prepared from: 207 ¹H-NMR (400 MHz, CD₃OD) 7.99-7.87 (m,4H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.54-7.52 (m, 2H), 3.81 (m, 1H),3.32 (s, 2H), 2.57 (s, 3H), 2.18 (m, 4H), 1.72 (m, 4H). ¹³C-NMR (100MHz, CD₃OD) 135.1, 134.1, 130.5, 129.3, 128.6, 127.8, 127.7, 127.6,125.2, 67.5, 61.9, 35.4, 30.2, 30.1. LC-MS (M + 1)⁺ 270.0.4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (227)

H H CH₃ OH H F2 Prepared from: 208 ¹H-NMR (400 MHz, CDCl₃) 7.92-7.82 (m,4H), 7.59-7.47 (m, 3H), 3.77 (m, 1H), 2.66 (s, 2H), 2.61 (d, J = 13.5Hz, 2H), 2.29 (s, 3H), 1.97- 1.88 (m, 2H), 1.65 (t, J = 13.5 Hz, 2H),1.42-1.20 (m, 4H). LC-MS (M + 1)⁺ 270.1.4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (228)

H CH₃ CH₃ OH H F Prepared from: 208 ¹H-NMR (400 MHz, CD₃OD) 8.11-7.89(m, 4H), 7.70 (d, J = 9.0 Hz, 1H), 7.60-7.51 (m, 2H), 3.72 (m, 1H), 3.52(brs, 2H), 2.69 (d, J = 13.0 Hz, 2H), 2.57 (s, 6H), 2.00-1.72 (m, 4H),1.50-1.32 (m, 2H). LC-MS (M + 1)⁺ 284.1.4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (229)

H CH₃ CH₃ H OH C Prepared from: 207 ¹H-NMR (400 MHz, CD₃OD) 7.90-7.77(m, 4H), 7.63 (d, J = 9.0 Hz, 1H), 7.52-7.41 (m, 2H), 3.73 (m, 1H), 2.72(s, 2H), 2.25-2.12 (m, 2H), 2.09-1.91 (m, 2H), 1.95 (s, 6H), 1.82-1.60(m, 4H). LC-MS (M + 1)⁺ 284.1.1-(4-chloro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine(230)

H CH₃ CH₃ Cl H C Prepared from: 211 ¹H-NMR (400 MHz, CDCl₃) 7.91-7.82(m, 4H), 7.55 (dd, J = 9.0, 1.5 Hz, 1H), 7.52-7.47 (m, 2H), 4.06 (m,1H), 2.42 (s, 2H), 2.18-2.01 (m, 4H), 2.04 (s, 6H), 1.83-1.71 (m, 4H).LC-MS (m/z) 302.3. 1-methyl-4-(1-(methylamino)ethyl)-4-(naphthalen-2-yl)cyclohexanol (231)

CH₃ H CH₃ CH₃ OH I, F2 Prepared from the corresponding nitrile.Enantiomers (E1, E2) separated by SFC w/AD column and 30% MeOH/0.1% DEA,280 nm. ¹H-NMR (400 MHz, CD₃OD) 7.93-7.84 (m, 4H), 7.63 (d, J = 8.5 Hz,1H), 7.55-7.45 (m, 2H), 2.59 (q, J = 7.0 Hz, 1H), 2.44-2.22 (m, 1H),2.23 (s, 3H), 2.18-2.03 (m, 2H), 1.66-1.23 (m, 5H), 1.04 (d, J = 7.0 Hz,3H), 1.01 (s, 3H). LC-MS (M + 1)⁺ 298.1.1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine (232)

H H CH₃ F H F2 Prepared from: 212 ¹H-NMR (400 MHz, CDCl₃) 7.87-7.81 (m,4H), 7.54-7.45 (m, 3H), 4.74 (m, 0.5H), 4.61 (m, 0.5H), 2.70 (s, 2H),2.52 (m, 2H), 2.25 (s, 3H), 2.01-1.94 (m, 2H), 1.76-1.56 (m, 4H).¹³C-NMR (100 MHz, CDCl₃) 133.7, 132.1, 128.8, 128.3, 127.6, 126.4,126.3, 126.1, 124.7, 92.8, 91.1, 63.7, 42.0, 37.3, 31.2, 31.1, 28.7,28.5. LC-MS (M + 1)⁺ 272.2.1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine(233)

H CH₃ CH₃ F H C Prepared from: 212 ¹H-NMR (400 MHz, CDCl₃) 7.82 (m, 4H),7.54 (dd, J = 8.5, 2.0 Hz, 1H), 7.45 (m, 2H), 4.71 (m, 0.5H), 4.58 (m,0.5H), 2.45 (m, 2H), 2.42 (s, 2H), 2.00 (s, 6H), 1.97 (m, 2H), 1.77-1.57(m, 4H). ¹³C-NMR (100 MHz, CDCl₃) 133.7, 132.0, 128.2, 128.1, 127.6,126.3, 126.0, 125.7, 125.5, 93.4, 91.7, 72.2, 48.7, 30.9, 30.8, 28.8,28.6. LC-MS (M + 1)⁺ 286.4.4-(1-(dimethylamino)ethyl)-1-methyl-4-(naphthalen-2- yl)cyclohexanol(234)

CH₃ CH₃ CH₃ CH₃ OH I, C Prepared from the corresponding nitrile.Enantiomers (E1, E2) separated by Chiral HPLC, AD column, 280 nm,90/10/0.1 hexanes/isopropanol/diethylamine. ¹H-NMR (400 MHz, CDCl₃)7.83-7.79 (m, 4H), 7.61 (m, 1H), 7.49- 7.43 (m, 2H), 3.01 (q, J = 7.5Hz, 1H), 2.82 (brd, J = 13.0 Hz, 1H), 2.62 (brs, 1H), 2.23 (d, J = 13.5Hz, 1H), 2.00 (s, 6H), 2.00-1.85 (m, 1H), 1.59-1.40 (m, 4H), 1.30-1.21(m, 1H), 1.02 (s, 3H), 0.84 (d, J = 7.0 Hz, 3H). ¹³C-NMR (100 MHz,CDCl₃) 133.5, 132.0, 128.3, 127.5, 127.3, 125.9, 125.7, 69.6, 44.0,42.5, 35.5, 35.2, 31.2, 29.7, 28.6, 11.7, 7.6. LC-MS (M + 1)⁺ 312.3.1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine(235)

H CH₃ CH₃ H F C Prepared from: 213 ¹H-NMR (400 MHz, CDCl₃) 7.81 (m, 4H),7.55 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 4.72 (m, 0.5H), 4.60 (m, 0.5H),2.46 (s, 2H), 2.22 (d, J = 13.5 Hz, 2H), 2.05-1.91 (m, 4H), 1.96 (s,6H), 1.69-1.56 (m, 2H). ¹³C- NMR (100 MHz, CDCl₃) 133.6, 132.0, 128.2,127.9, 127.6, 126.3, 126.0, 125.8, 125.7, 90.8, 89.1, 73.2, 48.7, 28.7,27.8, 27.6. LC-MS (M + 1)⁺ 286.2.1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine (236)

H H CH₃ H F A Prepared from: 213 ¹H-NMR (400 MHz, CDCl₃) 8.27 (brs, 1H),7.89-7.83 (m, 4H), 7.53- 7.49 (m, 3H), 4.73 (m, 0.5H), 4.61 (m, 0.5H),2.84 (s, 2H), 2.34 (d, J = 13.5 Hz, 2H), 2.30 (s, 3H), 2.08-1.96 (m,4H), 1.54 (t, J = 13.0 Hz, 2H). LC-MS (M + 1)⁺ 272.2.4-(benzo[d][1,3]dioxol-5-yl)-4-((methylamino)methyl)cyclohexanol (237)

H H CH₃ H OH F2 Prepared from: 214 ¹H-NMR (400 MHz, CDCl₃) 6.87 (d, J =2.0 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H),5.94 (s, 2H), 3.76 (m, 1H), 2.65 (s, 2H), 2.29 (s, 3H), 2.08-2.02 (m,2H), 1.82-1.70 (m, 4H), 1.62-1.56 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃)145.8, 119.8, 108.2, 107.3, 101.1, 68.7, 62.2, 41.4, 37.5, 30.8, 30.5.LC-MS (M + 1)⁺ 264.1. 4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)cyclohexanol (238)

H CH₃ CH₃ H OH F Prepared from: 214 ¹H-NMR (400 MHz, CD₃OD) 6.88 (s,1H), 6.81 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.0, 2.0 Hz, 1H), 5.92 (s,2H), 3.78 (m, 1H), 2.39 (s, 2H), 2.04-1.99 (m, 2H), 1.99 (s, 6H),1.78-1.67 (m, 4H), 1.58 (m, 2H). ¹³C- NMR (100 MHz, CD₃OD) 120.1, 108.0,107.8, 101.0, 70.7, 68.4, 48.5, 31.7, 30.3, 30.0. LC-MS (M + 1)⁺ 278.2.4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-((methylamino)methyl)cyclohexanol (239)

H H CH₃ CH₃ OH F2 Prepared from: 215 ¹H-NMR (400 MHz, CD₃OD) 8.45 (brs,1H), 6.98 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H),5.97 (s, 2H), 3.03 (s, 2H), 2.56 (s, 3H), 2.14 (d, J = 13.5 Hz, 2H),1.91 (t, J = 13.0 Hz, 2H), 1.55 (d, J = 13.5 Hz, 2H), 1.34 (t, J = 13.0Hz, 2H), 1.07 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD) 168.2, 149.2, 147.2,132.9, 120.9, 108.5, 108.4, 107.5, 101.5, 68.0, 62.4, 40.5, 34.1, 34.0,29.8, 29.0, 28.8. LC-MS (M + 1)⁺ 278.3.4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-methylcyclohexanol (240)

H CH₃ CH₃ CH₃ OH C Prepared from: 215 ¹H-NMR (400 MHz, CD₃OD) 8.54 (brs,1H), 6.99 (d, J = 1.5 Hz, 1H), 6.95 (dd, J = 8.5, 1.5 Hz, 1H), 6.84 (d,J = 8.5 Hz, 1H), 5.96 (s, 2H), 2.92 (s, 2H), 2.34 (s, 6H), 2.12 (d, 13.0Hz, 2H), 1.89 (t, J = 13.5 Hz, 2H), 1.53 (d, J = 13.0 Hz, 2H), 1.37 (d,J = 13.5 Hz, 2H), 1.03 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD) 120.9, 108.2,107.8, 101.4, 72.9, 68.2, 46.5, 34.1, 29.8, 29.5. LC-MS (M + 1)⁺ 292.2.4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-((methylamino)methyl)cyclohexanol (241)

H H CH₃ OH CH₃ F Prepared from: 216 ¹H-NMR (400 MHz, CD₃OD) 8.39 (brs,1H), 7.00-6.86 (m, 3H), 5.96 (s, 2H), 3.22 (s, 2H), 2.58 (s, 3H), 2.17(m, 2H), 1.78-1.74 (m, 2H), 1.65-1.59 (m, 4H), 1.27 (s, 3H). ¹³C-NMR(100 MHz, CD₃OD) 149.0, 147.2, 120.0, 108.4, 106.9, 101.5, 39.7, 34.5,34.0, 30.3, 27.4. LC-MS (M + 1)⁺ 278.1.4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-methylcyclohexanol (242)

H CH₃ CH₃ OH CH₃ C Prepared from: 216 ¹H-NMR (400 MHz, CD₃OD) 8.54 (brs,1H), 7.00 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.5, 2.0 Hz, 1H), 6.83 (d,J = 8.5 Hz, 1H), 5.94 (s, 2H), 3.03 (s, 2H), 2.33 (s, 6H), 2.16 (m, 2H),1.73 (m, 2H), 1.57 (t, J = 6.0 Hz, 4H), 1.26 (s, 3H). ¹³C-NMR (100 MHz,CD₃OD) 120.1, 108.1, 107.3, 101.3, 46.4, 34.8, 30.9. LC-MS (M + 1)⁺292.1. 1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (243)

H H CH₃ CH₂F OH A Prepared from: 217 ¹H-NMR (400 MHz, CD₃OD) 8.50 (brs,1H), 7.99-7.87 (m, 4H), 7.63 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 2H),4.03 (s, 1H), 3.91 (s, 1H), 3.19 (s, 2H), 2.54 (s, 3H), 2.46 (d, J =13.5 Hz, 2H), 2.06 (t, J = 13.5 Hz, 2H), 1.62 (d, J = 13.5 Hz, 2H), 1.41(t, J = 13.5 Hz, 2H). ¹³C-NMR (100 MHz, CD₃OD) 136.0, 133.9, 132.9,129.4, 128.0, 127.3, 127.3, 126.4, 124.2, 90.6, 88.9, 69.3, 62.4, 41.1,34.1, 28.2, 28.1, 27.8. LC-MS (M + 1)⁺ 302.3.4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (244)

H CH₃ CH₃ CH₂F OH F Prepared from: 217 ¹H-NMR (400 MHz, CDCl₃) 7.81 (m,4H), 7.55 (dd, J = 8.5, 1.5 Hz, 1H), 7.47-7.44 (m, 2H), 4.08 (s, 1H),3.96 (s, 1H), 2.43 (s, 2H), 2.34 (d, J = 13.5 Hz, 2H), 2.01 (dt, J =13.5, 3.0 Hz, 2H), 1.98 (s, 6H), 1.61 (d, J = 14.0 Hz, 2H), 1.38 (dt, J= 13.5, 3.0 Hz, 2H). ¹³C-NMR (100 MHz, CDCl₃) 144.1, 133.7, 132.0,128.2, 128.0, 127.6, 126.6, 126.0, 126.9, 125.7, 91.7, 90.0, 74.3, 48.8,44.0, 29.2, 29.1, 28.4. LC-MS (M + 1)⁺ 316.2.1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (245)

H H CH₃ OH CH₂F A Prepared from: 218 ¹H-NMR (400 MHz, CD₃OD) 7.99-7.87(m, 4H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.53-7.51 (m, 2H), 4.39 (s,1H), 4.27 (s, 1H), 3.46 (s, 2H), 2.58 (s, 3H), 2.37-2.29 (m, 2H), 2.00(m, 2H), 1.86-1.79 (m, 2H), 1.65 (m, 2H). ¹³C-NMR (100 MHz, CD₃OD)129.2, 128.1, 127.3, 126.4, 126.3, 125.8, 123.5, 34.1, 28.9, 28.4, 28.3.LC-MS (M + 1)⁺ 302.3.4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (246)

H CH₃ CH₃ OH CH₂F F Prepared from: 218 ¹H-NMR (400 MHz, CDCl₃) 7.81 (m,4H), 7.54 (dd, J = 9.0, 1.5 Hz, 1H), 7.47-7.42 (m, 2H), 4.45 (s, 1H),4.33 (s, 1H), 2.54 (s, 2H), 2.25- 2.20 (m, 2H), 1.96 (s, 6H), 1.96-1.91(m, 2H), 1.78-1.63 (m, 4H). ¹³C- NMR (100 MHz, CDCl₃) 133.7, 132.0,128.3, 127.9, 127.5, 126.0, 125.7, 125.6, 125.3, 89.7, 88.0, 48.5, 29.8,29.7. LC-MS (M + 1)⁺ 316.4. 1-methyl-4-((methylamino)methyl)-4-(4-(trifluoromethoxy)phenyl)cyclohexanol (247)

H H CH₃ CH₃ OH F2 Prepared from: 219 ¹H-NMR (400 MHz, CD₃OD) 8.34 (brs,2H), 7.58 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 3.10 (s, 2H),2.58 (s, 3H), 2.20 (d, J = 13.0 Hz, 2H), 1.98 (dt, J = 13.5, 3.0 Hz,2H), 1.58 (d, J = 13.5 Hz, 2H), 1.29 (dt, J = 13.5, 3.0 Hz, 2H), 1.05(s, 3H). ¹³C-NMR (100 MHz, CD₃OD) 129.4, 127.3, 121.6, 67.8, 62.2, 40.5,34.1, 33.9, 29.7, 28.7. LC-MS (M + 1)⁺ 318.2.4-((dimethylamino)methyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)cyclohexanol (248)

H CH₃ CH₃ CH₃ OH C Prepared from: 219 ¹H-NMR (400 MHz, CDCl₃) 7.39 (d,8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 2.30 (s, 2H), 2.09 (d, J = 13.5Hz, 2H), 1.97 (s, 6H), 1.88 (dt, J = 13.5, 3.0 Hz, 2H), 1.52 (d, J =13.0 Hz, 2H), 1.34 (dt, J = 13.5, 3.5 Hz, 2H), 1.11 (s, 3H). ¹³C-NMR(100 MHz, CDCl₃) 129.0, 120.6, 48.7, 35.2, 29.4. LC-MS (M + 1)⁺ 332.3.4-((methylamino)methyl)-4-(4- (trifluoromethoxy)phenyl)cyclohexanol(249)

H H CH₃ H OH F2 Prepared from: 220 LC-MS (15 minute method) 6.57 min,(M + 1)+ 304.2 @ 6.75 min; ¹H-NMR (400 MHz, CD₃OD) 8.42 (brs, 1H), 7.58(d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 3.78-3.75 (m, 1H), 3.24(s, 2H), 2.59 (s, 6H), 2.09-2.01 (m, 4H), 1.65-1.62 (m, 4H). 13C-NMR(100 MHz, CD₃OD), 167.9, 128.9, 121.5, 66.1, 59.5, 40.2, 34.1, 28.9.4-((dimethylamino)methyl)-4-(4- (trifluoromethoxy)phenyl)cyclohexanol(250)

H CH₃ CH₃ H OH C Prepared from: 220 ¹H-NMR (400 MHz, CDCl₃) 7.38 (d, J =9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 3.81-3.78 (m, 1H), 2.42 (s, 2H),2.10-2.03 (m, 2H), 1.96 (s, 6H), 1.86-1.78 (m, 2H), 1.70-1.57 (m, 4H).¹³C-NMR (100 MHz, CDCl₃) 147.4, 128.5, 122.0, 120.6, 94.6, 70.6, 68.2,48.5, 42.2, 30.3, 30.1, 29.6. LC-MS (M + 1)⁺ 318.3.1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N- methylmethanamine(251)

H H CH₃ F F F2 Prepared from: 221 ¹H-NMR (400 MHz, CDCl₃) 7.89-7.79 (m,4H), 7.53-7.48 (m, 3H), 2.70 (s, 2H), 2.51 (d, J = 13.0 Hz, 2H), 2.26(s, 3H), 2.05-1.91 (m, 4H), 1.87-1.77 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃)139.9, 133.6, 132.2, 128.9, 128.2, 127.6, 126.5, 126.3, 126.2, 124.6,64.1, 42.0, 37.4, 31.0, 30.9, 30.8, 30.7, 30.5. LC-MS (M + 1)⁺ 290.3.1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine(252)

H CH₃ CH₃ F F F Prepared from: 221 ¹H-NMR (400 MHz, CDCl₃) 7.82 (m, 4H),7.53 (d, J = 8.5 Hz, 1H), 7.47 (m, 2H), 2.45 (apd, J = 10.0 Hz, 2H),1.97 (s, 2H), 2.05-1.89 (m, 4H), 1.97 (s, 6H), 1.85-1.74 (m, 2H).¹³C-NMR (100 MHz, CDCl₃) 128.3, 128.2, 127.6, 126.3, 126.2, 125.9,125.3, 72.4, 48.6, 31.0, 30.7, 30.5, 30.4. LC-MS (M + 1)⁺ 304.2.

3,4-Dichlorophenyl-Cyclohexylamine Analogs

TABLE 7 Summary of 3,4-Dichlorophenyl-Cyclohexylamine Analogs GeneralR^(b) R^(c) R³ R⁴ Procedure(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (253) F H H H W,BB, E ¹H NMR (400 MHz, CDCl₃) δ 8.02 (broad, 1 H), 7.46 (d, J = 8.0 Hz,1 H), 7.43 (s, 1 H), 7.19 (d, J = 8.0 Hz, 1H), 4.62 (m, 1 H), 2.83 (s, 2H), 2.26 (m, 2 H), 1.90 (m, 2 H), 1.58 (m, 4 H); ¹³C NMR (100 MHz,CDCl₃), δ 141.52, 133.57, 131,80, 131.39, 129.57, 126.66, 91.08, 89.37,49.49, 40.58, 30.02, 29.94, 27.92, 27.72; ESI MS m/z 276.1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N- dimethylmethanamine(254) F H CH₃ CH₃ W, BB, E, D Prepared from 253 ¹H NMR (400 MHz, CDCl₃)δ 8.31 (broad, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.14, 2.4 Hz, 1 H), 4.62 (m, 1 H), 2.68 (s, 2 H), 2.26(m, 2 H), 2.22 (s, 6 H), 1.95 (m, 2 H), 1.70 (t, J = 13.6 Hz, 1 H), 1.57(m, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 166.24, 144.8, 133.23, 130.88,129.44, 126.88, 91.90, 90.19, 70.43, 47.54, 41.98, 30.83, 30.74, 28.22,28.02; ESI MS m/z 304.(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (255) H OCH₃ H HW, EE, E ¹H NMR (400 MHz, CD₃OD) δ 7.46 (m, 2 H), 7.22 (d, J = 7.6 Hz, 1H), 6.69 (broad, 2 H), 3.31 (s, 3 H), 2.80 (s, 2 H), 1.91 (m, 4 H), 1.72(m, 1 H), 1.40 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 142.92, 133.53,131.78, 131.26, 129.46, 126.87, 75.16, 55.65, 50.76, 40.98, 28.54,25.77; ESI MS m/z 288.1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N- dimethylmethanamine(256) H OCH₃ CH₃ CH₃ W, EE, E, D Prepared from 255 ¹H NMR (400 MHz,CD₃OD) 7.46 (d, J = 2.8 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.23 (dd, J= 2.0, 8.4 Hz, 1 H), 3.32 (s, 3 H), 3.23 (m, 1 H), 2.34 (s, 2 H), 1.87(s, 6 H), 1.84 (m, 2 H), 1.78 (m, 2 H), 1.56 (m, 2 H), 1.48 (m, 2 H);¹³C NMR (100 MHz, CD₃OD) 141.57, 133.26, 131.56, 131.34, 130.02, 128.66,69.25, 50.70, 47.73, 40.57, 30.79, 30.31; ESI MS m/z 316.0.(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (257) OCH₃ H H HW, X, EE, E ¹H NMR (400 MHz, CD₃OD) δ 7.44 (m, 2 H), 7.20 (d, J = 7.6Hz, 1 H), 6.68 (broad, 2 H), 3.29 (s, 3 H), 2.82 (s, 1 H), 1.90 (m, 4H), 1.73 (m, 1 H), 1.43 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃), δ 141.92,133.33, 131.38, 131.14, 129.75, 126.99, 75.06, 55.90, 50.95, 41.23,28.43, 25.93; ESI MS m/z 288.1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N- dimethylmethanamine(258) OCH₃ H CH₃ CH₃ W, X, EE, E, D Prepared from 257 ¹H NMR (400 MHz,CD₃OD) 7.45 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.21 (dd, J= 2.4, 8.8 Hz, 1 H), 3.33 (s, 3 H), 3.25 (m, 1 H), 2.37 (s, 2 H), 1.96(s, 6 H), 1.91 (m, 2 H), 1.80 (m, 2 H), 1.66 (m, 2 H), 1.54 (m, 2 H);¹³C NMR (100 MHz, CD₃OD) 141.28, 133.16, 131.23, 131.24, 129.94, 127.56,69.15, 50.80, 47.64, 40.48, 30.89, 30.26; ESI MS m/z 316.0.1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N-methylmethanamine (259)OCH₃ H CH₃ H W, X, EE, E, A Prepared from 257 ¹HNMR (400 MHz, CDCl₃) δ7.42 (d, J = 2.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.19 (dd, J = 2.4,8.4 Hz, 1 H), 3.28 (s, 3 H), 3.25 (m, 1 H), 2.56 (s, 2 H), 2.32 (m, 1H), 2.29 (s, 3 H), 1.88 (m, 2 H), 1.56 (m, 1 H), 1.24 (m, 2 H); ¹³C NMR(100 MHz, CDCl₃) δ 144.76, 132.95, 132.95, 130.64, 130.29, 129.59,126.92, 78.96, 64.90, 55.79, 42.43, 37.48, 31.88, 29.93, 27.58; ESI MSm/z 302.1. (1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (260)H F H H W, X, BB, E ¹H NMR (400 MHz, CD₃OD) δ 8.4 (broad, 1 H), 7.65 (d,J = 2.0 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.42 (dd, J = 2.0, 8.4 Hz,1 H), 4.67 (d, J = 48.4 Hz, 1 H), 3.05 (s, 2 H), 2.18 (m, 2 H), 1.90 (m,4 H), 1.51 (m, 2 H), 1.49 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) δ 140.69,133.19, 131.44, 131.24, 129.78, 127.43, 140.00, 88.69, 87.02, 50.75,40.48, 27.37, 26.82, 26.61; ESI MS m/z 276.0.1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N- dimethylmethanamine(261) H F CH₃ CH₃ W, X, BB, E, D Prepared from 260 ¹H NMR (400 MHz,CD₃OD) 7.47 (d, J = 2.4 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J= 2.4, 8.8 Hz, 1 H), 4.60 (m, 1 H), 2.69 (s, 2 H), 2.26 (m, 2 H), 2.22(s, 6 H), 1.95 (m, 2 H), 1.70 (m, 2 H), 1.56 (m, 2 H); ¹³C NMR (100 MHz,CD₃OD) 141.28, 133.22, 131.24, 130.87, 129.44, 126.88, 91.90, 90.20,70.43, 47.54, 41.98, 30.83, 30.74, 28.22, 28.03; ESI MS m/z 274.0.4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (262) OH H H H W, X,E ¹H NMR (400 MHz, CD₃OD) 7.63 (d, J = 2.4 Hz, 1 H), 7.59 (d, J = 8.8Hz, 1 H), 7.40 (dd, J = 2.4, 8.8 Hz, 1 H), 3.66 (m, 1 H), 3.02 (s, 2 H),2.40 (m, 2 H), 1.86 (m, 2 H), 1.62 (m, 2 H), 1.24 (m, 2 H); ¹³C NMR (100MHz, CD₃OD) 141.28, 133.16, 131.23, 131.24, 129.94, 127.56, 69.15,50.80, 47.64, 40.48, 30.89, 30.26; ESI MS m/z 274.0.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (263) OH HCH₃ CH₃ W, X, E, D Prepared from 262 ¹H NMR (400 MHz, CD₃OD) 7.64 (d, J= 2.4 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.36 (dd, J = 2.4, 8.8 Hz, 1H), 3.55 (m, 1 H), 3.01 (s, 2 H), 2.24 (m, 2 H), 2.23 (s, 6 H), 1.79 (m,2 H), 1.67 (m, 2 H), 1.33 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) 141.11,133.06, 131.33, 131.31, 129.88, 127.76, 69.35, 51.82, 47.64, 45.78,40.32, 30.77, 29.16; ESI MS m/z 302.0.1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N-methylmethanamine (264)F H CH₃ H W, BB, E, A Prepared from 253 ¹H NMR (400 MHz, CDCl₃) δ 7.46(d, J = 2.0 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.23 (dd, J = 2.0, 8.4Hz, 1 H), 4.47 (d, J = 48.8 Hz, 1 H), 2.71 (s, 2 H), 2.34 (s, 3 H), 2.28(m, 2 H), 1.94 (m, 2 H), 1.59 (m, 4 H); ¹³C NMR (100 MHz, CDCl₃), δ144.46, 133.02, 130.69, 130.26, 129.47, 126.83, 90.63, 88.41, 64.91,48.67, 42.24, 37.56, 29.97, 28.75, 28.92, 28.39, 27.71, 27.41; ESI MSm/z 290.0. (1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)methanamine (265)OPh H H H W, X, E ¹H NMR (400 MHz, CD₃OD) 8.40 (broad, 1 H), 7.66 (d, J= 2.0 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.42 (dd, J = 2.0, 8.8 Hz, 1H), 7.22 (m, 2 H), 6.84 (m, 3 H), 4.43 (m, 1 H), 3.31 (s, 2 H), 2.40 (m,2 H), 2.01 (m, 2 H), 1.75 (m, 2 H), 1.49 (m, 2 H); ¹³C NMR (100 MHz,CD₃OD) 157.57, 141.57, 133.23, 131.37, 131.27, 129.69, 129.32, 127.32,120.79, 115.94, 74.26, 49.93, 48.52, 48.44, 40.45, 30.31, 27.01; ESI MSm/z 336.1. 1-(1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)-N,N-dimethylmethanamine (266) Oph H CH₃ CH₃ W, X, E, F Prepared from 265 ¹HNMR (400 MHz, CD₃OD) 7.46 (d, J = 2.0 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1H), 7.24 (m, 3 H), 6.90 (m, 1 H), 6.84 (m, 2 H), 4.25 (m, 1 H), 2.36 (s,2 H), 2.30 (m, 2 H), 2.08 (s, 6 H), 2.0 (m, 2 H), 1.70 (m, 2 H), 1.48(m, 2 H); ¹³C NMR (100 MHz, CD₃OD) 157.57, 141.527, 133.10, 132.68,130.45, 129.98, 129.67, 127.16, 120.92, 116.19, 75.87 72.52, 49.93,48.56, 48.44, 40.45, 31.40, 27.82; ESI MS m/z 378.0.(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)methanamine (267) F F H HCC, E ¹H NMR (400 MHz, CD₃OD) δ 8.4 (broad, 1 H), 7.67 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1 H), 7.43 (dd, J = 8.4, 2.4 Hz, 1 H), 3.10 (s,2 H), 2.40 (m, 2 H), 2.20 (m, 2 H), 1.90 (m, 2 H), 1.70 (m, 2 H); ¹³CNMR (100 MHz, CD₃OD) δ 133.43, 131.82, 137.41, 129.57, 127.20, 122.35,49.58, 47.60, 40.18, 30.05, 29.76, 29.51, 29.45; ESI MS m/z 294.0.1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N- methylmethanamine(268) F F CH₃ H CC, E, F Prepared from 267 to give 268 and 269, whichwere separated by silica gel column chromatography (ethylacetate/hexane/DEA = 1:4:0.1). ¹H NMR (400 MHz, CD₃OD) δ 8.5 (broad, 1H), 7.68 (d, J = 2.4 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.44 (dd, J =8.4, 2.4 Hz, 1 H), 3.20 (s, 2 H), 2.58 (s, 3 H), 2.40 (m, 2 H), 2.05 (m,2 H), 1.92 (m, 2 H), 1.70 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) δ 139.86,133.53, 131.96, 131.30, 129.54, 127.16, 122.46, 59.57,48.03, 40.24,34.09, 29.94, 29.80, 29.70, 29.45; ESI MS m/z 307.9.1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N,N-dimethylmethanamine (269) F F CH₃ CH₃ CC, E, F Prepared from 267 to give268 and 269, which were separated by silica gel column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1) ¹H NMR (400 MHz, CD₃OD) δ 7.58 (d,J = 2.4 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.37 (dd, J = 8.4, 2.4 Hz,1 H), 2.43 (s, 2 H), 2.30 (m, 2 H), 2.01 (s, 6 H), 1.98 (m, 2 H), 1.82(m, 2 H), 1.65 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) δ 139.86, 133.53,131.96, 131.30, 129.54, 127.16, 122.46, 59.57,48.03, 40.24, 34.09,30.41, 30.17, 29.90, 29.81; ESI MS m/z 322.0.1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N-methylmethanamine (270)

CH₃ H FF, E, F 270 and 271 were separated by silica gel columnchromatography (ethyl acetate/hexane/DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃Cl) δ 7.42 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.19 (dd,J = 2.4, 8.8 Hz, 1 H), 3.90 (m, 4 H), 2.59 (s, 2 H), 2.27 (s, 6 H), 2.18(m, 2 H), 1.82 (m, 2 H), 1.62 (m, 2 H), 1.46 (m, 2 H); ¹³C NMR (100 MHz,CD₃Cl) δ 132.84, 130.54, 130.31, 129.39, 126.72, 109.02, 64.48, 64.47,41.91, 37.57, 31.74, 31.35; ESI MS m/z 330.1.1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N,N-dimethylmethanamine (271)

CH₃ CH₃ FF, E, F 1H NMR (400 MHz, CD₃Cl) δ 7.44 (d, J = 2.4 Hz, 1 H),7.36 (d, J = 8.8 Hz, 1 H), 7.21 (dd, J = 2.4, 8.8 Hz, 1 H), 3.91 (m, 4H), 2.32 (s, 2 H), 2.13 (m, 2 H), 1.98 (s, 3 H), 1.80 (m, 2 H), 1.62 (m,2 H), 1.42 (m, 2 H); ¹³C NMR (100 MHz, CD₃Cl) δ 145.35, 132.38, 130.14,130.15, 129.62, 129.71, 127.11, 72.01, 64.48, 64.47, 48.58, 42.87,31.35; ESI MS m/z 344.1.4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (272) OH CH₃H H Y, E Stereoisomers (cis- and trans-) were separated aftermethylation (General Procedure S) by silica gel column chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent transformations wereperformed using one stereoisomer, respectively. ¹H NMR (400 MHz, CD₃OD)δ 8.22 (broad, 1 H), 7.33 (d, J = 2.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1 H), 2.85 (s, 2 H), 1.92 (m, 2 H), 1.51(m, 2 H), 1.40 (m, 4 H), 1.10 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD), δ133.18, 131.29, 130.92, 129.00, 126.27, 68.63, 40.14, 34.52, 29.62,28.171; ESI MS m/z 288.2.4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol(273) OH CH₃ CH₃ H Y, E, F Prepared from 272 to give 273 and 274, whichwere separated by silica gel column chromatography (ethylacetate/hexane/DEA = 1:4:0.1). ¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J =2.0 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.21 (dd, J = 2.0, 8.8 Hz, 1H), 2.65 (s, 2H), 2.30 (s, 3 H), 2.04 (m, 2 H), 1.74 (m, 2 H), 1.62 (m,2 H), 1.50 (m, 2 H), 1.28 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 132.79,130.48, 130.25, 129.01, 126.29, 69.90, 60.98, 41.42, 37.57, 35.66,30.60, 29.92, 29.17; ESI MS m/z 302.2.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1- methylcyclohexanol(274) OH CH₃ CH₃ CH₃ Y, E, F Prepared from 272 to give 273 and 274 whichwere separated by silica gel column chromatography (ethylacetate/hexane/DEA = 1:4:0.1). ¹H NMR (400 MHz, CD₃OD) δ 7.45 (d, J =2.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.22 (dd, J = 2.4, 8.8 Hz, 1H), 2.37 (m, 2 H), 2.20 (m, 2 H), 198 (m, 6 H), 1.76 (m, 2 H), 1.58 (m,2 H), 1.48 (m, 2 H), 1.28 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 132.32,130.07, 129.75, 129.38, 126.74, 70.25, 48.53, 35.94, 30.546, 28.49; ESIMS m/z 316.2.4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (275) CH₃ OHH H Y, E Stereoisomers (cis- and trans-) were separated aftermethylation (General Procedure S) by silica gel column chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent transformations wereperformed using one stereoisomer, respectively. ¹H NMR (400 MHz, CD₃OD)δ 8.5 (broad, 1 H), 7.02 (s, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.40 (d, J= 8.8 Hz, 1 H), 2.98 (s, 2 H), 2.18 (m, 2 H), 1.94 (m, 2 H), 1.58 (m, 2H), 1.28 (m, 2 H), 1.07 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 140.93,133.07, 131.19, 131.12, 129.92, 127.61, 67.90, 51.74, 40.64, 34.05,29.66, 28.60, 28.37; ESI MS m/z 288.2.4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol(276) CH₃ OH CH₃ H Y, E, F Prepared from 275 (General Procedure F) togive 276 and 277, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 7.43 (d, J = 2.0 Hz,1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.20 (dd,J = 8.8, 2.0 Hz, 1 H), 2.54 (s, 2 H), 2.27 (s, 3 H), 2.08 (m, 2 H), 1.90(m, 2 H), 1.52 (m, 2 H), 1.30 (m, 2 H), 1.11 (s, 3 H); ¹³C NMR (100 MHz,CD₃OD) δ 132.86, 130.56, 130.23, 129.63, 127.06, 69.68, 69.94, 42.40,37.56, 35.16, 31.05, 29.82; ESI MS m/z = 302.2.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1- methylcyclohexanol(277) CH₃ OH CH₃ CH₃ Y, E, F Prepared from 275 (General Procedure F) togive 276 and 277, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 7.44 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.21 (dd,J = 2.4, 8.8 Hz, 1 H), 7.21 (dd, J = 2.4, 8.8 Hz, 1 H), 2.28 (s, 2 H),2.04 (m, 2 H), 1.99 (s, 6 H), 1.85 (m, 2 H), 1.51 (m, 2 H), 1.30 (m, 2H), 1.09 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 132.37, 130.14, 129.92,129.73, 127.39, 73.73, 69.65, 48.72, 43.45, 35.15, 31.16, 29.32; ESI MSm/z = 316.2. 4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol(278) OH ethyl H H Y, E Stereoisomers (cis- and trans-) were separatedafter alkylation (General Procedure S) by silica gel columnchromatography (ethyl acetate/hexane = 1:15 to 1:7) and subsequenttransformations were performed using one stereoisomer, respectively. ¹HNMR (400 MHz, CD₃Cl) δ 7.40 (d, J = 2.4 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 2.4, 8.4 Hz, 1 H), 2.77 (s, 2 H), 2.12-1.94 (m, 2 H),1.90-1.74 (m, 2 H), 1.72-1.64 (m, 1 H), 1.61-1.50 (m, 3 H), 1.48-1.38(m, 1 H), 0.89 (t, J = 8.0 Hz, 3 H); ¹³C NMR (100 MHz, CD3Cl) δ 146.40,132.79, 130.54, 130.35, 129.14, 126.38, 71.21,49.55, 33.84, 32.94,29.34, 7.51; ESI MS m/z 302.2.4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol (279)OH ethyl CH₃ H Y, E, F Prepared from 278 (General Procedure F) to give279 and 280, which were separated by silica gel column chromatography(ethyl acetate/hexane/ DEA= 1:4:0.1). ¹H NMR (400 MHz, CD₃Cl) δ 7.64 (d,J = 2.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.41 (dd, J = 2.4, 8.4 Hz,1 H), 3.30 (s, 3 H), 2.58 (s, 2 H), 2.16-2.09 (m, 2 H), 1.84-1.76 (m, 2H), 1.68-1.50 (m, 6 H), 0.94 (t, J = 7.6 Hz, 3 H); ¹³C NMR (100 MHz,CD₃Cl) δ 133.02, 131.27, 131.08, 130.96, 128.96, 126.49, 69.96, 39.96,34.20, 31.90, 29.45, 6.33; ESI MS m/z 316.1.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol(280) OH ethyl CH₃ CH₃ Y, E, F Prepared from 278 (General Procedure F)to give 279 and 280, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 7.60 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.40 (dd,J = 2.4, 8.8 Hz, 1 H), 2.83 (s, 2 H), 2.16 (s, 6 H), 2.12-2.00 (m, 2 H),1.86-1.74 (m, 2 H), 1.64-1.46 (m, 6 H), 0.92 (t, J = 7.2 Hz, 3 H); ¹³CNMR (100 MHz, CD₃OD) 132.20, 130.26, 130.25, 129.94, 129.17, 126.84,70.45, 46.79, 41.18, 32.33, 29.86, 6.40; ESI MS m/z 330.0.4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol (281) ethylOH H H Y, E Stereoisomers (cis- and trans-) were separated afteralkylation (General Procedure S) by silica gel column chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent transformations wereperformed using one stereoisomer, respectively. ¹H NMR (400 MHz, CD₃OD)δ 7.63 (d, J = 2.0 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.40 (dt, J =2.0, 8.4 Hz, 1 H), 2.98 (s, 2 H), 2.18 (d, J = 13.2 Hz, 2 H), 1.90 (dt,J = 2.8, 13.6 Hz, 2 H), 1.36 (d, J = 13.2 Hz, 2 H), 1.32 (q, J = 7.6 Hz,2 H), 1.21 (td, J = 2.8, 13.6 Hz, 2 H), 0.81 (t, J = 7.6 Hz, 3 H); ¹³CNMR (100 MHz, CD₃OD) δ 140.68, 133.11, 131.27, 131.15, 129.95, 127.63,69.95, 51.88, 40.89, 35.68, 31.72, 28.18; ESI MS m/z 284.1.4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol (282)ethyl OH CH₃ H Y, E, F Prepared from 281 (General Procedure F) to give282 and 283, which were separated by silica gel column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1). ¹H NMR (400 MHz, CD₃Cl) δ 7.63 (d,J = 2.0 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.43 (dd, J = 2.0, 8.4 Hz,1 H), 3.31 (s, 3 H), 2.56 (s, 2 H), 2.14-2.10 (m, 2 H), 1.82-1.78 (m, 2H), 1.66-1.51 (m, 6 H), 0.93 (t, J = 7.6 Hz ,3 H); ¹³C NMR (100 MHz,CD₃Cl) δ 133.22, 131.37, 131.28, 131.02, 129.10, 126.51, 69.87, 39.93,34.22, 32.40, 29.25; ESI MS m/z 316.1.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol(283) ethyl OH CH₃ CH₃ Y, E, F Prepared from 281 (General Procedure F)to give 282 and 283, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 7.54 (s, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.4 Hz,1 H), 2.37 (s, 2 H), 2.09 (d, J = 13.6 Hz, 1 H), 1.98 (s, 6 H), 1.86 (t,J = 14.0 Hz, 1 H), 1.50 (d, J = 14.0 Hz, 1 H), 1.28 (q, J = 6.8 Hz, 2H), 1.20 (t, J = 14.0 Hz, 1 H), 0.79 (t, J = 6.8 Hz, 3 H); ¹³C NMR (100MHz, CD₃OD) δ 145.17, 131.92, 130.03, 129.99, 129.38, 127.79, 73.89,70.62, 47.57, 43.26, 35.75, 32.09, 28.96; ESI MS m/z 332.1.4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-propylcyclohexanol (284)n-propyl OH H H Y, E ¹H NMR (400 MHz, CD₃OD) δ 7.63 (s, 1 H), 7.56 (d, J= 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 3.30 (s, 2 H), 2.15 (m, 2 H),1.84 (m, 2 H), 1.64 (m, 2 H), 1.54 (m, 2 H), 1.42 (m, 2 H), 0.95 (t, J =6.8 Hz, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 132.89, 131.13, 130.99, 129.09,126.67, 70.03, 43.61, 39.76, 32.37, 29.48, 29.18, 16.04, 13.94; ESI MSm/z 316.4.4-(3,4-dichlorophenyl)-4-((methylamino)methyl)-1-propylcyclohexanol(285) n-propyl OH CH₃ H Y, E, F Prepared from 284 (General Procedure F)to give 285 and 286, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 8.38 (broad, 1 H), 7.64 (d, J = 2.0 Hz, 1 H), 7.62 (d, J = 8.8Hz, 1 H), 7.41 (dd, J = 2.0, 8.8 Hz, 1 H), 3.34 (s, 2 H), 2.60 (s, 3 H),2.16 (m, 2 H), 1.82 (m, 2 H), 1.64 (m, 2 H), 1.52 (m, 2 H), 1.42 (m, 2H), 0.95 (t, J = 6.8 Hz, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 133.03,131.33, 131.11, 130.99, 129.06, 126.57, 69.94, 39.87, 34.01, 32.33,29.45, 29.14, 16.01, 15.96, 13.88; ESI MS m/z 330.2.4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1- propylcyclohexanol(286) n-propyl OH CH₃ CH₃ Y, E, F Prepared from 284 (General ProcedureF) to give 285 and 286, which were separated by silica gel columnchromatography (ethyl acetate/hexane/ DEA = 1:4:0.1). ¹H NMR (400 MHz,CD₃OD) δ 7.45 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.21 (dd,J = 2.0, 8.8 Hz, 1 H), 2.40 (s, 2 H), 2.02-1.94 (m, 2 H), 1.96 (s, 6 H),1.76 (m, 2 H), 1.60 (m, 2 H), 1.48 (m, 2 H), 1.40 (m, 2 H), 0.95 (t, J =6.8 Hz, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 132.25, 130.03, 129.69, 129.21,126.58, 71.52, 48.46, 43.59, 33.27, 30.08, 16.44, 14.92; ESI MS m/z344.2.

cis-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol (287)

299 to 287

The title compound was prepared from(1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol 299 (63 mg,0.230 mmol) according to General Procedure F2. The crude product waspurified by chromatography (SiO₂, MeOH/CH₂Cl₂, 0:100 to 10:90) to give(1s,4s)-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol (40mg, 61%) as clear oil. ¹H NMR (400 MHz, CDCl₃): δ 1.57-1.72 (m 4H),1.78-1.83 (m, 2H), 2.04-2.11 (m, 2H), 2.30 (s, 3H), 2.68 (s, 2H),3.78-3.82 (m, 1H), 7.20 (dd, J=8.4, 2.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H),7.44 (s, 1H). ESI MS m/z 288.

(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-cyclohexanol(288)

299 to 288

The title compound was prepared from(1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (PharmaCore,63 mg, 0.230 mmol) according to General Procedure F2. The crude productwas purified by reverse phase HPLC (C-18 column, CH₃CN/water, CH₃CN from5% to 100%) to give(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (50mg, 75%). ¹H NMR (400 MHz, CDCl₃): δ 1.57-1.68 (m 4H), 1.77-1.86 (m,3H), 1.99 (s, 6H), 2.00-2.08 (m, 1H), 2.41 (s, 2H), 3.79-3.82 (m, 1H),7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.45 (s, 1H). ¹³CNMR (100 MHz, CDCl₃): δ 29.5, 30.2, 42.4, 48.6, 68.0, 70.4, 126.8,129.4, 129.7, 130.1, 132.3, 147.1. ESI MS m/z 302.

4-(3,4-Dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (289)

To a solution of 270 (20 mg, 0.060 mmol) in acetone-H₂O (1:1, 1.5 mL)was added TsOH—H₂O (12 mg, 0.060 mmol). The reaction mixture was stirredovernight before being concentrated. The residue was dissolved in MeOH(1 mL) and subjected to reverse phase column chromatography(CH₃CN:H₂O:0.1% formic acid=5% to 100%) to give4-(3,4-dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (8.5 mg, 50%).ESI MS m/z 286.1.

trans-4-(aminomethyl)-4-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclo-hexanamine(290)

To a solution of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile(600 mg, 2.22 mmol) in MeOH (10 mL) was added MeNH₂.HCl (1.0 M in THF,4.44 mL, 4.44 mmol), HCO₂H (0.2 mL) and NaB(CN)H₃ (420 mg, 6.66 mmol).The reaction mixture was stirred overnight before being concentrated.The residue was dissolved in MeOH (2 mL) and subjected to reverse phasecolumn chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to givethe mixture of cis- and trans-isomers (446 mg, 71%), which wereseparated (OD column, ethanol:methanol:hexane:DEA=3:2:95:0.1) to givethe cis-analog (88 mg) and the trans-analog (332 mg).

To a solution of the above trans-analog (200 mg, 0.71 mmol) in CH₂Cl₂ (5mL) was added pyridine (0.5 mL) and acetyl chloride (80.3 mg, 72.2 μL,1.06 mmol). The reaction mixture was stirred for 2 h before beingquenched with saturated NH₄Cl. The product was extracted with CH₂Cl₂ (20mL×2), dried and concentrated. The residue was subjected to silica gelcolumn chromatography (ethyl acetate/hexane=1:10 to 1:1) to givetrans-1-(3,4-dichlorophenyl)-4-(ethyl(methyl)amino)cyclohexanecarbonitrile(202 mg, 88%).

The title compound was synthesized from the above nitrile (150 mg, 0.46mmol) according to General Procedure E. The crude product was dissolvedin MeOH (2 mL) and subjected to reverse phase column chromatography(CH₃CN:H₂O:0.1 formic acid=5% to 100%) (77 mg, 76%). ESI MS m/z 315.2.

(±) (1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (291)

The unsaturated amine (1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile)was prepared according to General Procedure BB and was formed togetherwith the monofluorinated intermediate in a 1:1 ratio.

To a 1M solution of LAH in THF (0.2 ml, 0.184 mmol), which was dilutedup to 1 ml with Et₂O, was added a solution of1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile (0.043 g, 0.184 mmol) inEt₂O (2 ml) and the resulting mixture was stirred at 35° C. for 16 h.The reaction was then quenched with K₂CO₃ (sat. aq., 5 ml). It wasextracted with EtOAc (2×25 ml) and the combined organic phases weredried over Na₂SO₄, decanted and the solvent was removed in vacuo to givethe product (0.042 g, 96%), which was pure by HPLC.

The corresponding HCl salt was prepared by the addition of 2M HCl (Et₂O)to the free amine. After stirring for 1 h, the white precipitate wasfiltered off to afford pure(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine. LC-MS (m/z+) 238.1.

(±) N-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (292)

The title compound was formed as a byproduct in the reduction of thefluorinated carbamate. Preparative HPLC separation (chiralpak-AD column,95:2.5:2.5:0.1 Hexanes:EtOH:MeOH:HNEt₂) afforded the crude product,which was converted to the corresponding HCl salt by the addition of 2MHCl (Et₂O) to the free amine. After stirring for 1 h, the whiteprecipitate was filtered off to afford pureN-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine hydrochloridesalt (0.021 g). ¹H-NMR (400 MHz, CDCl₃) δ 9.04 (brs, 1H), 8.67 (brs,1H), 7.79-7.67 (m, 4H), 7.45 (m, 3H), 5.80 (d, J=8.0 Hz, 1H), 5.59 (d,J=7.5 Hz, 1H), 3.21 (brs, 1H), 3.12 (brs, 1H), 2.89 (m, 1H), 2.57 (m,1H), 2.22-1.99 (m, 2H), 2.15 (s, 6H), 1.75 (m, 2H). ¹³C-NMR (100 MHz,CDCl₃) δ 138.6, 133.5, 132.6, 129.1, 128.6, 127.7, 127.2, 126.9, 126.6,126.5, 124.3, 59.7, 40.0, 35.6, 33.7, 31.4, 22.5. LC-MS (m/z+) 252.1.

N,N-dimethyl(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (293)

The title compound was prepared from 292 according to General ProcedureC (0.023 g, 49% yield). ¹H-NMR (400 MHz, CDCl₃) δ 7.81-7.74 (m, 4H),7.54 (dd, J=9.0, 2.0 Hz, 1H), 7.46-7.41 (m, 2H), 5.82 (m, 1H), 5.60(apd, J=10.0 Hz, 1H), 2.70 (d, J=13.0 Hz, 1H), 2.63 (d, J=17.5 Hz, 1H),2.53 (d, J=13.5 Hz, 1H), 2.43 (m, 1H), 2.02 (m, 2H), 1.98 (s, 6H),1.72-1.70 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ 132.0, 128.3, 127.5,127.2, 125.8, 125.8, 125.6, 125.5, 125.4, 70.8, 48.5, 34.4, 31.9, 22.9.LC-MS (m/z+) 266.1.

4′,8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1′-cyclohexan]-4′-ol(diastereomer 1) (294)

The title compound was isolated as a byproduct in the Eschweiler-Clarkalkylation (General Procedure C) of the amine 215. The two products wereseparated by reverse phase preparative HPLC (CH₃CN:H₂O) to afford theproduct as the formate salt: ¹H-NMR (400 MHz, CHCl₃) δ 8.42 (brs, 1H),6.57 (s, 1H), 5.92 (s, 1H), 3.91 (s, 2H), 3.18 (s, 2H), 2.79 (s, 3H),1.92-1.87 (m, 2H), 1.74-1.60 (m, 6H), 1.39 (s, 3H). LC-MS (m/z+) 290.3.

4′,8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1′-cyclohexan]-4′-ol(Diastereomer 2) (295)

The title compound was isolated as a byproduct in the Eschweiler-Clarkalkylation (General Procedure C) of the amine 216. The two products wereseparated by reverse phase preparative HPLC (CH₃CN:H₂O). ¹H-NMR (400MHz, CD₃OD) δ 8.38 (brs, 1H), 7.02 (s, 1H), 6.59 (s, 1H), 5.93 (s, 2H),4.07 (s, 2H), 3.34 (s, 2H), 2.91 (s, 3H), 2.23-2.19 (m, 2H), 1.65-1.53(m, 6H), 1.26 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD) δ 106.2, 101.6, 58.1,56.5, 43.6, 33.7, 32.4, 30.1. LC-MS (M+1) 290.2.

2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine (296)

(a)(R)-N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide

A flame dried flask under N₂ was charged with anhydrous Et₂O (5 mL) and(1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 5.6 mL, 2.8 mmol)and cooled to −78° C.(R,E)-N-((1-(3,4-dichlorophenyl)cyclohexyl)methylene)-2-methylpropane-2-sulfinamide(460 mg, 1.28 mmol) in anhydrous Et₂O (3 mL) was added dropwise and thesolution was stirred at −78° C. for 1 h, then allowed to warm to RTovernight. After 20 h sat'd aqueous Na₂SO₄ solution (4 mL) was added andthe suspension was filtered, dried (Na₂SO₄), filtered and concentrated.Purification on the Biotage with a 25M column and an ethylacetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100%EtOAc for 5 CV) gave the pure title compound (300 mg, 49%) as a clearoil. HPLC R_(t)=2.62 min; ¹H NMR (400 MHz, CDCl₃) 7.45-7.43 (m, 2H),7.24-7.22 (d, J=8.43 Hz, 1H), 4.44-4.42 (m, 1H), 4.11-4.04 (m, 2H),3.75-3.67 (m, 2H), 3.11-3.01 (m, 2H), 2.64 (d, J=12.8 Hz, 1H), 2.27 (d,J=13.9 Hz, 1H), 2.04-1.99 (m, 1H), 1.88-1.44 (m, 8H), 1.33-1.19 (m,12H), 0.93-0.80 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) 141.8, 132.7, 130.8,130.4, 130.2, 128.4, 101.7, 66.8, 66.3, 57.1, 46.2, 34.3, 32.5, 26.1,25.7 (d), 23.1, 22.2, 21.8; LC-MS 10.5 min, (M+1)⁺ 476 @ 10.6 min.

(b) 2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine formate

The above sulfinamide (58 mg, 0.13 mmol) was dissolved in wet acetone (3mL) and 6 M HCl (1 mL) was added. The clear reaction was stirred for 16h, poured into 6 M HCl and washed with Et₂O (2×10 mL). The Et₂O washeswere discarded. The aqueous phase was made basic (pH=10-11) with sat'daqueous K₂CO₃, at which point a white precipitate appeared. The basicaqueous phase was washed with EtOAc (4×20 mL) and the EtOAc washes werecombined, dried (Na₂SO₄), filtered and concentrated. The crude imine wasdissolved in anhydrous THF (4 mL) in a product vial and polymer boundcyanoborohydride (Argonaut, 2.43 mmol/g, 327 mg, 0.796 mmol) and glacialacetic acid (35 mL, 0.597 mmol) were added. The slightly yellow clearsolution was shaken at RT for 16 h and filtered. The resin was washedwith CH₂Cl₂ and the combined washes were concentrated. The crude aminewas dissolved in MeOH (3 mL) and purified on the Gilson with thestandard method. Fractions containing the major peak (Rt˜3.4 min) wereconcentrated on the Genevac and combined to give the title compound as aformate salt (37 mg, 31%). HPLC R_(t)=1.5 min; ¹H NMR (400 MHz, CDCl₃)8.45 (s, 1H), 7.48 (d, J=1.83 Hz, 1H), 7.45 (d, J=8.43 Hz, 1H),7.28-7.26 (m, 1H), 3.48-3.43 (m, 1H), 3.17-3.11 (m, 1H), 3.04-2.98 (m,1H), 2.31 (d, J=12.8 Hz, 2H), 1.84-1.51 (m, 10H), 1.26-1.16 (m, 2H); ¹³CNMR (100 MHz, CDCl₃) 168.1, 141.2, 133.3, 131.2, 131.0, 130.5, 127.8,69.4, 45.3, 43.7, 33.1, 31.0, 25.9 (d), 23.6, 21.8 (d); LC-MS 8.35 min,(M+1)⁺ 298 @ 8.51 min.

2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine (297)

(a) Synthesis of(R)-N-(3-(1,3-dioxan-2-yl)-1-(1-(naphthalen-2-yl)cyclohexyl)propyl)-2-methylpropane-2-sulfinamide

A flame dried flask under N₂ was charged with anhydrous Et₂O (3 mL) and(1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 6.78 mL, 3.39mmol) and cooled to −78° C.(R,E)-2-methyl-N-((1-(naphthalen-2-yl)cyclohexyl)methylene)propane-2-sulfinamide(524 mg, 1.54 mmol) in anhydrous Et₂O (3 mL) was added dropwise and thesolution was stirred at −78° C. for 1 h, then allowed to warm to RTovernight. After 20 h sat'd aqueous Na₂SO₄ solution (4 mL) was added andthe suspension was filtered, dried (Na₂SO₄), filtered and concentrated.Purification on the Biotage with a 25M column and an ethylacetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100%EtOAc for 5 CV) gave the title compound (581 mg, 83%) as a clear oil.HPLC (JPK method) R_(t)=2.61 min; ¹H NMR (400 MHz, CDCl₃) 7.85-7.80 (m,4H), 7.53 (d, J=8.8 Hz, 1H), 7.48-7.45 (m, 2H), 4.38 (t, J=5.13 Hz, 1H),4.10-3.99 (m, 2H), 3.77-3.62 (m, 2H), 3.25 (d, J=8.8 Hz, 1H), 3.15-3.10(m, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.51 (d, J=11.7 Hz, 1H), 2.03-1.90 (m,2H), 1.64-1.59 (m, 4H), 1.49-1.42 (m, 2H), 1.31-1.23 (m, 4H), 1.12 (s,9H), 0.87-0.83 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) 138.5, 133.6, 132.0,128.2, 128.1, 127.5, 126.9, 126.2, 126.0, 102.1, 67.0, 66.7, 57.0, 46.4,35.0, 34.8, 32.8, 26.2 (d), 25.9, 23.3, 22.6, 22.2; LC-MS 10.4 min,(M+1)⁺ 458 @ 10.6 min.

(b) Synthesis of 2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine formate

The above sulfinamide (317 mg, 0.694 mmol) was dissolved in wet acetone(12 mL) and 6 M HCl (4 mL) was added. The clear reaction was stirred for16 h, poured into 6 M HCl and washed with Et₂O (2×20 mL). The Et₂Owashes were discarded. The aqueous phase was made basic (pH=10-11) withsat'd aqueous K₂CO₃, at which point a white precipitate appeared. Thebasic aqueous phase was washed with EtOAc (4×30 mL) and the EtOAc washeswere combined, dried (Na₂SO₄), filtered and concentrated. The crudeimine was dissolved in anhydrous THF (7 mL) in a product vial andpolymer bound cyanoborohydride (Argonaut, 2.43 mmol/g, 697 mg, 1.69mmol) and glacial acetic acid (73 mL, 1.27 mmol) were added. Theslightly yellow clear solution was shaken at RT for 16 h and filtered.The resin was washed with CH₂Cl₂ and the combined washes wereconcentrated. The crude amine was dissolved in MeOH (3 mL) and purifiedon the Gilson with the standard method. Fractions containing the majorpeak (Rt˜3.4 min) were concentrated on the Genevac and combined to givethe title compound as the formate salt (96 mg, 49%). HPLC R_(t)=1.58min; ¹H NMR (400 MHz, CDCl₃) 8.51 (s, 1H), 7.88-7.78 (m, 4H), 7.55-7.52(dd, J=1.47, 8.80 Hz, 1H), 7.48-7.42 (m, 2H), 3.61-3.57 (m, 1H),3.04-2.99 (m, 1H), 2.86-2.82 (m, 1H), 2.56-2.53 (m, 2H), 1.84-1.53 (m,9H), 1.39-1.25 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) 168.3, 137.7, 133.6,132.2, 128.7, 128.3, 127.8, 127.4, 126.3, 126.2, 125.5, 69.5, 45.2,43.8, 33.4, 31.1, 26.0 (d), 23.6, 22.0 (d); LC-MS 8.14 min, (M+1)⁺ 280 @8.23 min.

Example 5 Scaled-Up Syntheses of 225, 93, 48 E1 and 277 5.1. Scaled-upSynthesis of(1s,4s)-4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol(225) 5.1.1. General

Reagents and solvents were used as received from commercial suppliers.Proton and carbon nuclear magnetic resonance spectra were obtained on aBruker AC 300 spectrometer at 300 and 75 MHz, respectively.High-pressure liquid chromatography was performed on an Agilent 1100series instrument. Gas chromatography-mass spectroscopy was performed ona Hewlett-Packard G1800A GCD System.

Compound 225 was prepared following the procedures outlined in Scheme33, below.

5.1.2. Preparation of dimethyl 4-cyano-4-(naphthalen-2-yl)heptanedioate

A 3-L, three-necked flask equipped with a temperature probe, refluxcondenser, addition funnel and overhead stirrer was charged with2-naphthylacetonitrile (300 g, 1.79 mol), methylacrylate (600 mL, 6.65mol) and tert-butanol (900 mL). A solution of tetrabutylammoniumhydroxide (1 M; 75 mL, 75 mmol) in methanol was added slowly through anaddition funnel over a period of 30 min (Note: Highly exothermic). Theresulting clear solution was stirred at 70° C. for 2 h and assayed byTLC (3:7 EtOAc/Heptane; stained using Hanessian solution) and GC. Thereaction mixture was cooled to room temperature before beingconcentrated under reduced pressure. The residue was partitioned between2 M HCl (1 L) and MTBE (4 L). The phases were separated and the aqueousphase was extracted with MTBE (500 mL). The combined organic phases werewashed with brine (1 L), dried over MgSO₄, filtered and concentratedunder reduced pressure at 40-45° C. to give a residue which was passedthrough a bed of silica (1:4 EtOAc/Heptane) to yield the title compound[569 g, 93%, 100% (AUC) by GC] as an off-white solid. ¹H NMR (CDCl₃, 300MHz): δ 7.75 (2 d merged, 2H), 7.45 (dd, 1H), 3.5 (s, 6H), 2.4-2.2 (m,6H), 2.15-1.98 (m, 2H).

5.1.3. Preparation of methyl5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate

A 12-L, three-neck flask equipped with a temperature probe, refluxcondenser, addition funnel and overhead stirrer was charged withpotassium tert-butoxide (365 g, 3.2 mol) and toluene (2.4 L). A solutionof dimethyl 4-cyano-4-(naphthalen-2-yl)heptanedioate (500 g, 1.4 mol) intoluene (4 L) was added through an addition funnel. The reaction mixturewas heated to 90° C. and stirred for 1.5 h. The progress of the reactionwas monitored by TLC (3:7 EtOAc:Heptane). The reaction mixture wascooled to 20° C. and quenched slowly with 2 M HCl (2 L) and extractedwith EtOAc (4 L). The phases were separated and the organic phase waswashed with brine (2×1 L), dried over MgSO₄, filtered and concentratedunder reduced pressure at 40-45° C. to yield compound 9 (546 g, 120%) asa yellow solid. It was taken into the next step without furtherpurification. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.1 (s, 1H), 8.0-7.9 (m, 4H),7.7 (dd, 1H), 7.5 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.7 (s, 3H), 3.4(s, 1H), 3 (d, 1H), 2.9-2.6 (m, 2H), 2.5 (d, 1H), 2.8-2.5 (m, 2H),2.48-2.3 (m, 6H).

5.1.4. Preparation of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile

A 12-L, four-neck flask equipped with a temperature probe, refluxcondenser and overhead stirrer was charged with methyl5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate (600 g, 1.9mol), brine (1 L) and DMSO (6 L). The mixture was heated to 135° C. andstirred for 12 h. The progress of the reaction was monitored by TLC (2:3EtOAc/Heptane). After 12 h, the reaction mixture was cooled to roomtemperature, diluted with water (6 L) and extracted twice with MTBE (5L, 3 L). The combined organic phases were washed with brine (4×3 L),dried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure at 40-45° C. to give a residue which was trituratedwith heptane/MTBE (1:1, 2 L). The resulting slurry was stirred for 2 h,filtered and dried under high vacuum for 12 h to yield the titlecompound (301 g, 62%) as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz):δ 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.8 (dd, 1H), 7.6 (m, 2H), 7.3 (dd, 1H),7.2 (m, 1H), 3.1 (s, 1H), 2.8 (m, 2H), 2.2-2.6 (m, 8H), 1.2 (s, 2H).

5.1.5. Preparation ofcis-4-hydroxy-4-methyl-1-(naphthalen-2-yl)cyclohexanecarbonitrile

A dried 5-L, three-neck flask equipped with a temperature probe,addition funnel, nitrogen line and overhead stirrer was charged with 1 Msolution of MeLi in ether (800 mL, 1.23 mol) using canula underanhydrous atmosphere. (Note: MeLi is highly flammable; strictlyanhydrous conditions are required.) The solution was cooled to −70° C.and added to a solution of1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile (160 g, 0.642 mol) inanhydrous THF (1,600 mL) slowly over a period of 40 min maintaining thetemperature below −50° C. The mixture was stirred at −70° C. for 1 h.Progress of the reaction was monitored by TLC (2:3 EtOAc/Heptane) andGC. The reaction was cautiously quenched with saturated ammoniumchloride solution (700 mL) when the starting material was <15% by GC.The typical ratio of starting material:(a):(b) by GC was 1:7:2. Thedesired cis-nitrile (a) was a major and more polar compound by TLC. Thereaction mixture was gradually warmed to room temperature and dilutedwith EtOAc (500 mL), DI water (200 mL), and the mixture was stirred for5 min. The phases were separated and the aqueous phase was extractedwith EtOAc (500 mL). The combined organic phases were washed with brine(1 L), dried over MgSO₄, filtered and concentrated under reducedpressure at 40-45° C. to afford a residue which was purified bychromatography (10-40% EtOAc in heptane). The pure fractions of mostpolar compound by TLC were pooled and concentrated to yield thecis-nitrile (a) [88.5 g, 52%, 99% (AUC) by GC] as an off-white solid. ¹HNMR (DMSO-d₆, 300 MHz): δ 8.1 (s, 1H), 8.0-7.8 (m, 3H), 7.75 (dd, 1H),7.58 (2H, dd), 4.65 (s, 1H), 2.3-2.0 (m, 4H), 1.8 (dt, 2H), 1.68 (dd,2H), 1.2 (s, 3H).

5.1.6. Preparation ofcis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol

A dried 5-L, three-neck flask equipped with a temperature probe,addition funnel, nitrogen line and overhead stirrer was charged with 1.0M solution of BH₃.THF (1.29 L, 1.29 mol) using canula under anhydrousatmosphere. (Note: BH₃.THF is highly flammable; strictly anhydrousconditions are required.) The solution was cooled to 10° C. and added toa solution of nitrile (a) (114 g, 0.429 mol) in anhydrous THF (1.2 L)slowly over period of 30 min maintaining the temperature below 25° C.The mixture was stirred at room temperature for 16 h. The reaction wascautiously quenched with 6 M HCl (250 mL) until pH 1-2. (Note: Evolutionof hydrogen gas; proper vent was needed). The reaction mixture wasconcentrated under reduced pressure to give a residue which was dilutedwith MTBE (600 mL) and water (300 mL). The precipitated boron salts werefiltered and the phases of filtrate were separated. The aqueous phasewas adjusted to pH 9-10 using 6 M NaOH solution and extracted withdichloromethane (3×400 mL). The combined organic phases were washed withbrine (300 mL), dried over MgSO₄, filtered and concentrated underreduced pressure at 40-45° C. to yield the primary amine (92.1 g, 80%)as a foamy solid which was taken into next step without furtherpurification. ¹H NMR (CD₃OD, 300 MHz): δ 7.95-7.8 (m, 4H), 7.6 (d, 1H),7.5-7.4 (m, 2H), 2.7 (s, 2H), 2.3 (dd, 2H), 1.9 (dt, 2H), 1.6 (dd, 2H),1.4 (dt, 2H), 1.05 (s, 3H).

5.1.7. Preparation of 225

A 3-L, three-neck flask equipped with a temperature probe, nitrogenline, condenser, heating mantle and overhead stirrer was charged withcis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (92 g,0.341 mol), 37% aqueous formaldehyde (300 mL), formic acid (46 mL) andwater (300 mL). The mixture was heated to 85° C. and stirred overnight.(Note: Gas evolution (CO₂) was observed at 60° C.) The reaction wasmonitored by TLC (9:1 DCM/MeOH). After 16 h, the reaction mixture wascooled to room temperature, diluted with water (400 mL) and washed withheptane (2×300 mL). The aqueous phase was adjusted to pH 2.0 using 6 MHCl and washed with dichloromethane (2×100 mL). The aqueous phase wasadjusted to pH 9-10 using 6 M NaOH and extracted with dichloromethane(3×400 mL). The combined organic phases were washed with brine (500 mL),dried over MgSO₄, filtered and concentrated under reduced pressure at40-45° C. to yield 225 (71.1 g, 70.3%) as a off-white solid, which wastaken into salt formation step without further purification. ¹H NMR(CDCl₃, 300 MHz): δ 7.92-7.8 (m, 4H), 7.65 (d, 1H), 7.5-7.4 (m, 2H),2.45 (s, 2H), 2.3 (dd, 2H), 1.99 (s and dd merged, 8H), 1.6 (dd, 2H),1.5 (dt, 2H), 1.1 (s, 3H).

5.1.8. Preparation of 225 Hydrochloride

A 2-L, three-neck flask equipped with a temperature probe, heatingmantle, nitrogen line and overhead stirrer was charged with 225 (83 g,0.28 mol), ethanol (300 mL) and heated to 50° C. until a clear solutionwas obtained. The solution was cooled to room temperature and added to asolution of 2 M HCl in ether (150 mL) slowly over period of 10 min. Theprecipitated solids were stirred for 1 h at room temperature andfiltered. The cake was washed with mixture of MTBE/EtOH (2:1, 100 mL),dried overnight under high vacuum to provide 225 hydrochloride [60.4 g,66%, 97.7% (AUC) by HPLC]. ¹H NMR (CD₃OD, 300 MHz): δ 8.1 (m, 4H), 0.7.7(d, 1H), 7.6 (dd, 2H), 3.5 (s, 2H), 2.55 (s, 6H), 2.45 (dd, 2H), 2.1(dt, 2H), 1.75 (dd, 2H), 1.5 (dt, 2H), 1.1 (s, 3H). ¹³C NMR (CD₃OD, 300MHz): δ 138.1, 135.3, 134.3, 130.8, 129.7, 129.2, 128.9, 128.1, 126.2,73.3, 69.5, 47.5, 42.8, 35.6, 31.3, 30.89.

5.2. Scaled-Up Synthesis ofN-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)methanamine (93)

The title compound was synthesized according to Scheme 34, below.

5.2.1. Synthesis of 2-Naphthylacetonitrile

To a stirred solution of sodium cyanide (10.5 g, 0.214 mol) in H₂O (20mL) was added a solution of 2-(bromomethyl)naphthalene (40.0 g, 0.181mol) in EtOH (170 mL). The resulting mixture was heated at reflux for 3h, then spin-evaporated in vacuo. The residue was partitioned betweenH₂O (175 mL) and CH₂Cl₂ (200 mL). The aqueous layer was furtherextracted with CH₂Cl₂ (3×200 mL). The combined organic layers were driedover MgSO₄ (5 g) and spin-evaporated in vacuo to a solid. The solid wasdissolved in refluxing EtOH (100 mL). The clarified solution was storedat 3° C. for 16 h. Solids were collected by filtration and dried toconstant weight in vacuo to give 24.8 g (81.9%) of product suitable forfurther transformation. A total of 257.2 g of material was prepared inthis fashion.

5.2.2. Synthesis of 1-(2-Naphthyl)cyclohexanecarbonitrile

To a stirred suspension of NaH (12.0 g, 0.3 mol) (60 wt % oildispersion) in DMSO (480 mL) was added a solution of 1 (20.0 g, 0.120mol) in DMSO (120 mL) dropwise, in a thin stream. The resulting mixturewas stirred at 25° C. for 1 h. The mixture was cooled to 15° C. and1,5-dibromopentane (41.2 g, 0.179 mol) was added dropwise, whilemaintaining the temperature at ≦22° C. The resulting mixture was stirredat 25° C. for 18 h. The mixture was cooled to 15° C. and quenched withsat. aq. NH₄Cl (100 mL). The resulting mixture was partitioned betweenH₂O (1.2 L) and t-butyl methyl ether (MTBE) (300 mL). The aqueous layerwas further extracted with MTBE (200 mL). The combined organic layerswere washed with brine (200 mL), dried over MgSO₄ (5 g) andspin-evaporated in vacuo to an oil. The oil was chromatographed on asilica gel column (1.0 kg) packed in, and eluted with hexanes-EtOAc(4:1) (8.0 L). Appropriate fractions as determined by TLC were combinedand spin-evaporated in vacuo to an oil, which solidified when pumpeddown, giving 27.4 g (97.0%) of purified product. A total of 240.2 g ofproduct suitable for further transformation was prepared in thisfashion.

5.2.3. Synthesis of 1-(2-Naphthyl)cyclohexanecarboxaldehyde)

To a cold (−78° C.), stirred mixture of 2 (140.9 g, 0.5988 mol) intoluene (1.85 L) was added diisobutylaluminum hydride (DIBAL-H) (1.0 Min toluene) (1.273 L) dropwise, at such a rate as to maintain thetemperature at ≦−65°. The resulting mixture was stirred at −78° C. for 3h. EtOAc (1.5 L) was added, followed by the dropwise addition of aq. 1 MHCl (1.5 L). The resulting mixture was filtered to remove gelatinoussolids. The biphasic filtrate was separated. The filter cake was washedwith EtOAc (3×500 mL). The combined organic layer was washed with brine(500 mL), dried over MgSO₄ (20 g) and spin-evaporated in vacuo to give127.0 g (89.0%) of product suitable for further transformation. A totalof 197.7 g of product was prepared in a similar fashion.

5.2.4. Synthesis of N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine

To a stirred solution of 3 (127.0 g, 0.5329 mol) in 2.0 M methylamine(in THF) (1.8 L, 3.6 mol) was added 20 drops of acetic acid. Theresulting mixture was stirred at 25° C. for 3 h. Potassium borohydride(64.2 g, 1.19 mol) was added, and stirring at 25° C. was continued for18 h. The mixture was quenched by the careful addition of aq. 1 M HCl topH˜2. The resulting biphasic mixture was separated. The organic layerwas extracted with aq. 1 M HCl (2×500 mL). The combined aqueous layerswere basified with 6 M NaOH to pH˜10, and extracted with EtOAc (3×1.0L). The combined organic layers were washed with brine (750 mL), driedover MgSO₄ (20 g) and spin-evaporated in vacuo to give 88.4 g (65.5%) ofcrude free-base as an oil. This material was combined with 61.3 g ofsimilar material and chromatographed on a silica gel pad (1.5 kg) packedin and eluted with CH₂Cl₂-MeOH (6:1) (12.2 L). Appropriate fractions asdetermined by TLC were combined and spin-evaporated in vacuo to give141.0 g (94.2% recovery) of an oil. The oil was dissolved in CH₂Cl₂ (500mL). A solution of 1.0 M HCl (in Et₂O) (600 mL) was slowly added withstirring. The resulting suspension was filtered. The solids weresuspended in warm (38° C.) CH₂Cl₂ (500 mL), then re-collected byfiltration and dried to constant weight in vacuo at 25° C. to give 91.1g of 93 HCl salt, mp; 228-230° C. (dec., uncorrected).

5.3. Scaled-Up Asymmetric Synthesis of 48 E1

The title compound was prepared via asymmetric synthesis according tothe synthetic route outlined in Scheme 35, below. The absoluteconfiguration of the chiral center a to the amine was not determined.Rather, the final material was correlated via chiral HPLC to anauthentic sample of 48 E1 and 48 E2 and the intermediates were assignedby analogy.

5.3.1. Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone

A 2 L round bottom flask was charged with a magnetic stir bar and 100.8g (396.6 mmol) of 1-(3,4-dichloro-phenyl)-cyclohexanecarbonitrile andwas flushed with N₂. The solid was then dissolved with 960 mL of drytoluene and the mixture was cooled to −78° C. The chilled homogeneoussolution was then treated with 300 mL of a 1.6 M solution of MeLi (inEt₂O). The resulting pale yellow solution was allowed to slowly warm tor.t. and left to stir for 12 h. The mixture was then chilled to −20° C.and quenched with 2 N HCl. The biphasic mixture was extracted with MTBE(2×). The combined organic layers were washed sequentially with asaturated solution of K₂HCO₃ and brine before drying over Na₂SO₄. Thedried mixture was filtered and all volatiles were removed under reducedpressure to give 107.5 g (396.6 mmol) of the title compound as a paleyellow oil in >90% purity (as determined by reverse phase LCMS). Thismaterial was used in subsequent steps without further purification: ¹HNMR (400 MHz, CDCl₃) δ 7.41-7.39 (m, 2H), 7.14 (d, 1H, J=8.4 Hz),2.31-2.28 (m, 2H), 1.91 (s, 3H), 1.79-1.74 (m, 2H), 1.69-1.54 (m, 3H),1.51-1.41 (m, 2H), 1.35-1.26 (m, 1H).

5.3.2. Synthesis ofN-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide

A mixture of 10.53 g (38.8 mmol) of1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethanone (7.02 g, 57.9 mmol) of(R)-TBSA, 16.1 mL of Ti(OEt)₄ and 80 mL of anhydrous toluene was heatedto 110° C. under an atmosphere of N₂ for 2 days. The mixture was cooledto rt and poured into a vigorously stirred solution of brine and theresulting biphasic mixture was extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The resulting residue was chromatographed on SiO₂using Hexanes/EtOAc (9:1) to afford 9.5 g (65%) of the title compound:¹H NMR (300 MHz, CDCl₃) δ 7.43-7.39 (m, 2H), 7.17 (dd, 1H, J=8.7, 2.4Hz), 2.25-2.15 (m, 2H), 2.06 (s, 3H), 1.95-1.88 (m, 2H), 1.61-1.50 (m,6H), 1.31 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 187.1, 144.2, 133.1, 131.2,130.8, 129.3, 126.7, 57.1, 53.9, 34.5, 34.3, 26.0, 22.92, 22.89, 22.7,19.7.

5.3.3. Synthesis ofN-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethyl)-2-methylpropane-2-sulfinamide

2-Methyl-propane-2-sulfinic acid{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide: 56 g (149.6 mmol)of 2-Methyl-propane-2-sulfinic acid{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethylidene}-amide was dissolvedin 1 L of THF. The solution was chilled to −20° C. and treated with 49 g(190 mmol) of Cp₂ZrHCl. The mixture was allowed to warm to rt and leftto stir overnight before cooling back to −20° C. and quenching with asaturated solution of NH₄Cl. The mixture was warmed to rt extracted withEtOAc (3×). The combined organic layers were washed with H₂O, brine andthen dried over Na₂SO₄. All volatiles were then removed under reducedpressure. The resulting mixture was suspended in MTBE and filtered. Allvolatiles were again removed under reduced pressure to give 54 g (96%)of the title compound as a white solid in >90% chemical purity and wasused without further purification. The diastereomeric ratio wasdetermined to be >98% (reverse phase HPLC: Symmetry C18 column; solventgradiant using H₂O:ACN with 0.05% TFA): ¹H NMR (300 MHz, CDCl₃) δ7.45-7.41 (m, 2H), 7.20 (dd, 1H, J=8.6, 2.3 Hz), 3.34-3.25 (m, 1H), 3.01(d, 1H, J=6.9 Hz), 2.50-2.44 (m, 1H), 2.23-2.17 (m, 1H), 1.65-1.48 (m,5H), 1.34-1.17 (m, 3H), 1.13 (s, 9H), 0.98 (d, 3H, J=6.6 Hz); ¹³C NMR(75 MHz, CDCl₃) δ 141.9, 132.8, 131.1, 130.6, 130.4, 128.5, 60.6, 56.1,46.5, 33.7, 33.0, 26.6, 22.8, 22.3, 22.1, 16.8.

5.3.4. Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine

54 g (143.5 mmol) of 2-Methyl-propane-2-sulfinic acid{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide was dissolved in300 mL of MeOH, cooled to 0° C. and 300 mL of a 4N HCl solution (indioxane) was added. After 3 h, the solution was concentrated underreduced pressure. The resulting slurry was suspended in 1.2 L of Et₂Oand left to stir over night at rt before collecting the solid byfiltration. The resulting pale yellow solid was washed with Et₂O anddried. The solid was dissolved in CH₂Cl₂ and washed with a 20% K₂HCO₃.The organic layer was isolated, washed with brine and concentrated underreduced pressure to yield 38 g (97%) of 2 E1 in >99% ee (Chiralpak AD,using heptane/EtOH/DEA 95:5:0.1 as the eluent).

5.3.5. Synthesis ofN-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethyl)formamide

N-{1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethyl}-formamide: 50 g (184.4mmol) of 1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethylamine was dissolvedin 1 L of ethylformate and left to stir under an N₂ atmosphere for 24 hbefore removing all volatiles under reduced pressure. The resultingsolid was filtered through a plug of SiO₂ (using CH₂Cl₂/MeOH (20:1) asthe eluent) to afford 51.32 g (93%) of the title compound after theremoval of all volatiles. This material was used in the subsequent stepwithout further purification.

5.3.6. Synthesis of1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine hydrochloride(48 E1)

To the refluxing solution ofN-{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-formamide (5.2 g, 17.32mmol) in anhydrous THF (75 mL) was added slowly BH₃.SMe₂ (2N solution inTHF, 26 mL, 51.96 mmol). The solution was stirred at 70° C. for 20 minsthen a distillation head was installed. The solution was refluxed for 2h, during which SMe₂ was distilled, and the solution was cooled to R.T.and concentrated using a rotary evaporator. The pale yellow residue wascooled to 0° C. and added slowly to methanol (20 mL) to destroy theexcess borane. The resulting clear solution was added to 6N aqueous HCl(50 mL) and heated to reflux for 40 minutes, then cooled to roomtemperature. The solid that formed was filtered and washed with water(2×50 mL), followed by slurrying in ethyl ether (200 mL) and filtrationto give 48 E1 as a white solid. (4.04g, 72.5%). Note: Same reaction wasrun on a 50g scale with 70% yield.

5.4. Scaled-Up Synthesis of 277 5.4.1. General Experimental Details

Reagents and solvents were used as received from commercial suppliers.Proton and carbon nuclear magnetic resonance spectra were obtained on aBruker AC 300 spectrometer at 300 and 75 MHz, respectively.High-pressure liquid chromatography was performed on an Agilent 1100series instrument. Gas chromatography-mass spectroscopy was performed ona Hewlett-Packard G1800A GCD System.

5.4.2. Synthesis of dimethyl4-cyano-4-(3,4-dichlorophenyl)-heptanedioate

To a 2-L, three-neck flask equipped with a temperature probe, refluxcondenser, addition funnel and overhead stirrer was charged with3,4-dichlorophenylacetonitrile (100 g, 0.54 mol), methylacrylate (139.56g, 1.62 mol) and tert-butanol (475 mL). To the mixture was added veryslowly (highly exothermic) 1.0 M solution of tetrabutylammoniumhydroxide (11 mL, 0.011 mol) in methanol. After the addition wascomplete, the temperature rose from 21.1° C. to 68.4° C. The resultingclear solution was stirred at 70° C. for 2 h and assayed by TLC (3:7EtOAc/Heptane; stained using Hanessian solution) and GC. The reactionmixture was cooled to room temperature before being concentrated underreduced pressure. The residue was partitioned between 2 M HCl (500 mL),brine (200 mL) and MTBE (1.5 L). The phases were separated and theaqueous phase was extracted with MTBE (250 mL). The combined organicphases were washed with brine (500 mL), dried over MgSO₄ and filtered.The filtrate was concentrated under reduced pressure at 40-45° C. toyield the title compound [192.1 g, 99%, 100% (AUC) by GC] as anoff-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.75 (m, 2H), 7.45 (dd,1H), 3.5 (s, 6H), 2.4-2.2 (m, 6H), 2.15-1.98 (m, 2H).

5.4.3. Synthesis of methyl5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate

To a 12-L, three-neck flask equipped with a temperature probe, refluxcondenser, addition funnel and overhead stirrer was charged withpotassium tert-butoxide (266 g, 2.3 mol) and toluene (1 L). A solutionof dimethyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (402 g, crude,386 g theoretical, 1.07 mol) in toluene (3 L) was added through anaddition funnel. The reaction mixture was heated to 90° C. and stirredfor 1 h. The progress of the reaction was monitored by TLC (4:6EtOAc/Heptane; stained using Hanessian solution). After 1 h, thereaction mixture was cooled to 15° C. and quenched slowly with 2 M HCl(2.3 L). The phases were separated and the aqueous phase was extractedwith MTBE (1 L). The combined organic phases were washed with brine (2×1L), dried over MgSO₄, filtered and concentrated under reduced pressureat 40-45° C. to yield the title compound (424 g, >100%) as a yellowsolid. The crude was taken into next step without further purification.¹H NMR (CDCl₃, 300 MHz): δ 7.8 (d, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 3.7(s, 3H), 2.9 (d, 1H), 2.8-2.5 (m, 3H), 2.4-2.3 (m, 3H).

5.4.4. Synthesis of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile

To 12-L, four-neck flask equipped with a temperature probe, refluxcondenser and overhead stirrer was charged with methyl5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate (424 g,crude, 350 g theoretical, 1.07 mol), brine (500 mL) and DMSO (3.4 L).The mixture was heated to 135° C. and stirred for 12 h. The progress ofthe reaction was monitored by TLC (4:6 EtOAc/Heptane; stained usingHanessian solution). The reaction mixture was cooled to room temperatureand combined with the crude mixture from a previous 145 g batchreaction, diluted with water (6 L), extracted with MTBE (6 L), and thenEtOAc/MTBE (3:5, 8 L). The organics were combined and washed with brine(4×2.5 L), dried over MgSO₄, filtered and concentrated under reducedpressure at 40-45° C. to afford a residue which was triturated withheptane/MTBE (1:1, 1.2 L). The resulting slurry was stirred for 0.5 h,filtered and dried under high vacuum for 2 h to afford the titlecompound [313 g, 77% over 2 steps, 100% (AUC) by GC] as an off-whitesolid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.9 (d, 1H), 7.75 (dd, 1H), 7.6 (dd,1H), 2.8-2.5 (m, 2H), 2.48-2.3 (m, 6H).

5.4.5. Synthesis of1-(3,4-dichlorophenyl)-4-hydroxy-4-methylcyclohexanecarbonitrile

To a dry 5-L, three-neck flask equipped with a temperature probe,addition funnel, nitrogen line and overhead stirrer was charged with 1.0M solution of MeLi in ether (680 mL, 1.04 mol) using canula underanhydrous atmosphere (Note: MeLi is highly flammable; strictly anhydrousconditions are required). The solution was cooled to −70° C. and added asolution of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile (198 g,0.738 mol) in anhydrous THF (1,600 mL) slowly over a period of 45 minwhile maintaining the temperature below −50° C. The mixture was stirredat −70° C. for 1 h. The progress of the reaction was monitored by TLC(2:3 EtOAc/heptane; stained using Hanessian solution) and GC. Thereaction was cautiously quenched with saturated ammonium chloridesolution (700 mL) when starting material was <15% by GC. The typicalratio of starting material:(a):(b) by GC was 3.1:70.5:26.4. The desiredcis-nitrile (a) was a major and more polar compound by TLC. The reactionmixture was diluted with EtOAc (600 mL), DI water (300 mL), and stirredfor 5 min. The phases were separated and the aqueous phase was extractedwith EtOAc (600 mL). The combined organic phases were washed with brine(1 L), dried over MgSO₄ and filtered. The filtrate was concentratedunder reduced pressure at 40-45° C. to yield a residue which waspurified by chromatography (10-40% EtOAc in heptane). The pure fractionsof most polar compounds by TLC were pooled and concentrated to yield thecis nitrile (a) [114 g, 54.5%, 100% (AUC) by GC] as an off-white solid.¹H NMR (DMSO-d₆, 300 MHz): δ 7.85 (s, 1H), 7.7 (d, 1H), 7.55 (dd, 1H),4.6 (s, 1H), 2.15-1.85 (m, 4H), 1.8 (dt, 2H), 1.6 (dd, 2H), 1.15 (s,3H).

5.4.6. Synthesis ofcis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol

To a dry 5-L, three-neck flask equipped with a temperature probe,addition funnel, nitrogen line and overhead stirrer was charged with 1.0M solution of BH₃.THF (980 mL, 0.984 mol) using canula under anhydrousatmosphere (Note: BH₃.THF is highly flammable; strictly anhydrousconditions are required). The solution was cooled to 10-15° C. and addedto a solution of the cis-nitrile (a) (114 g, 0.401 mol) in anhydrous THF(1,400 mL) slowly over a period of 30 min while maintaining thetemperature below 25° C. The mixture was stirred at room temperatureovernight. The reaction was cautiously quenched with 6 M HCl (300 mL)until pH 2-2.0. The reaction mixture was concentrated under reducedpressure and the residue was taken into a 5-L flask equipped withoverhead stirrer and addition funnel. DI water (500 mL) was added intothe flask and adjusted pH to 9-10 using 6 M NaOH solution. The aqueousphase was extracted with dichloromethane (3×500 mL). The combinedorganic phases were taken into another 5-L flask and charged slowly with6 M HCl (400 ml). The precipitated HCl salt was filtered and thefiltrate was taken into a separating funnel. The aqueous phase was takeninto a 5-L flask and charged with water (2 L) and the HCl salt. The pHof the mixture was adjusted to 9-10 using 6 M NaOH solution andextracted with dichloromethane (2 L). The combined organic phases werewashed with brine (1 L), dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure at 40-45° C. to yield the titlecompound (104 g, 90%) as a foamy solid which was taken into next stepwithout further purification. ¹H NMR (CD₃OD, 300 MHz): δ 7.45 (d and smerged, 2H), 7.25 (dd, 1H), 2.5 (s, 2H), 1.95 (dt, 2H), 1.7 (ddd, 2H),1.45 (dt, 2H), 1.15 (ddd, 2H), 0.9 (s, 3H).

5.4.7. Synthesis of4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol(277)

To a 3-L, three-neck flask equipped with a temperature probe, nitrogenline and overhead stirrer was charged withcis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (99 g,0.343 mol), 37% aqueous formaldehyde (80 mL), formic acid (80 mL) andcooled to 5-10° C. Sodium cyanoborohydride (72 g, 1.14 mol) was added inportions and stirred for 1 h at room temperature. The progress of thereaction was monitored by TLC (9:1:0.1 DCM/MeOH/TEA). After 2 h, thereaction was not complete. Additional 37% aqueous formaldehyde (3.2 mL),formic acid (3.2 mL), and sodium cyanoborohydride (2.88 g, 4.58 mmol)was added. The reaction was quenched with 6 M NaOH solution (100 mL) andconcentrated under reduced pressure to give a residue which was dilutedwith dichloromethane (2 L), 6 M NaOH solution (500 mL), and brine (500mL). The phases were separated and the aqueous phase was extracted withdichloromethane (1 L). The combined organic phases were dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at40-45° C. to yield 277 (104 g, 96%) as an off-white solid which wastaken into salt formation step without further purification. ¹H NMR(CDCl₃, 300 MHz): δ 7.45 (s, 1H), 7.4 (d, 1H), 7.2 (dd, 1H), 2.3 (s,2H), 2.05 (dd, 1H), 2.0 (s, 6H), 1.9 (ddd, 2H), 1.55 (dd, 2H), 1.3 (m,3H), 1.1 (s, 3H).

5.4.8. Preparation of4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol277 hydrochloride

To a 3-L, three-neck flask equipped with a temperature probe, nitrogenline and overhead stirrer was charged with free base of 277 (crude fromprevious reaction, 0.328 mol) and ethanol (500 mL). The mixture washeated to 50° C. until a clear solution was obtained. The solution wascooled to room temperature and added to a solution of 2 M HCl in ether(200 mL) slowly. After 5 min, precipitation of HCl salt was observed.The slurry was stirred for 1 h at room temperature and filtered. Thecake was washed with a mixture of MTBE/EtOH (2:1, 200 mL) and dried overnight under high vacuum to yield 277 hydrochloride [80.8 g, 70%, 98.0%(AUC) by HPLC]. ¹H NMR (D₂O, 300 MHz): δ 7.65 (d, 1H), 7.55 (d, 1H), 7.5(dd, 1H), 3.5 (s, 2H), 2.5 (s, 6H), 2.15 (dd, 2H), 1.85 (dt, 2H), 1.5(dd, 2H), 1.3 (dt, 2H), 0.05 (s, 3H).

Example 6 In Vitro Analyses Monoamine Uptake Assays

The compounds of the invention were tested for their inhibition offunctional uptake of serotonin (5-HT), norepinephrine (NE), and dopamine(DA), in synaptosomes prepared from rat whole brain, hypothalamus, orcorpus striatum, respectively, and/or using recombinant humantransporters, as described herein, below. Compounds were initiallytested at 10 μM in duplicate. Compounds showing ≧50% inhibition ofuptake were further tested at 10 different concentrations in duplicatein order to obtain full inhibition curves. IC₅₀ values (concentrationinhibiting control activity by 50%) were then determined by nonlinearregression analysis of the inhibition curves. Results are summarized inTable 8, below.

6.1. Serotonin Functional Uptake Assay for Rat Reuptake Transporter

Quantification of 5-HT uptake was performed using synaptosomes isolatedin a 0.32M sucrose buffer from a male Wistar rat cortex. The uptake ofradiolabelled 5-HT by synaptosomes (100 μg of proteins/point) wasallowed by incubating them in a well for 15 min at 37° C. in presence oftest compounds and [³H]5-hydroxytryptamine (serotonin; 0.1 μCi/point).

Synaptosomes and [³H]serotonin were prepared in a Krebs buffer pH 7.4containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated during 5 minutes before incubation.Basal control was incubated for 15 minutes at 4° C. in order to avoidany uptake. Following this incubation the uptake was stopped byfiltration through a unifilter 96-wells GFB Packard plate washed withKrebs buffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]serotonin. The radioactivity associated to the synaptosomes retainedon the unifilter corresponding to the uptake was then measured with amicroplate scintillation counter (Topcount, Packard) using ascintillation fluid. Nonspecific binding was measured in the presence ofan excess of cold, unlabeled ligand. Specific binding was obtained bysubtracting nonspecific binding from total binding.

The reference compound was imipramine tested at 10 concentrationsranging from 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See,Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

6.2. Serotonin Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human serotonin reuptake transporter was assayed using therecombinant human serotonin transporter expressed in HEK-293 cells usinga published method (Gu H et al., J. Biol. Chem. 1994, 269 (10):7124-7130). HEK-293 cells expressing human serotonin transporter wereplated before the assay. Test compound and/or vehicle was preincubatedwith cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at18 to 25° C. and 65 nM [³H]serotonin was then added for an additionaltimed incubation period (ten to thirty minutes). Cells with internalized[³H]serotonin were washed and the amount of tritium taken into cells iscounted using a liquid scintillation counter to determine [³H]serotoninuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM fluoxetine, and was subtracted from the countsfor assays to correct for non-specific binding of tritium. Reduction of[³H]serotonin uptake by 50 percent or more (50%) relative to anuninhibited control reaction indicates significant inhibitory activity.Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. The referencecompound for the assay was fluoxetine, for which the IC₅₀ value of 7.1nM was obtained in a typical experiment.

6.3. Dopamine Functional Uptake Assay for Rat Reuptake Transporter

Quantification of dopamine uptake was performed using synaptosomesisolated in a 0.32 M sucrose buffer from a male Wistar rat striatum. Theuptake of radiolabelled dopamine by synaptosomes (20 μg ofproteins/point) was allowed by incubating them for 15 minutes at 37° C.in the presence of test compounds and [³H]-dopamine (0.1 μCi/point). Theexperiment was performed in a deep well.

Synaptosomes and [³H]-dopamine were prepared in a Krebs buffer pH 7.4containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated for 5 minutes before incubation. Basalcontrol was incubated for 15 minutes at 4° C. in order to avoid anyuptake. Following this incubation, the uptake was stopped by filtrationthrough a unifilter 96-wells GFB Packard plate washed with Krebs buffercontaining 25 mM NaHCO₃ in order to eliminate free [³H]-dopamine. Theradioactivity associated to the synaptosomes retained onto the unifiltercorresponding to the uptake was then measured with a microplatescintillation counter (Topcount, Packard) using a scintillation fluid.

The reference compound was GRB 12909 tested at 8 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁶ M in order to obtain an IC₅₀ value. See, Jankowskyet al., J. Neurochem. 1986, 46:1272-1276).

6.4. Dopamine Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human dopamine reuptake transporter was assayed using therecombinant human dopamine transporter expressed in either CHO-K1 orHEK293 cells using a published method (Pristupa, Z. B. et al., Mol.Pharmacol. 45: 125-135, 1994). Either CHO-K1 or HEK293 cells expressinghuman recombinant dopamine transporter were plated before the assay.Test compound and/or vehicle was preincubated with cells in modifiedHEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C. and 50 nM[³H]dopamine was then added for an additional timed incubation period(10 to 30 minutes). After washing the cells to remove [³H]dopamine notinternalized, the cells were lysed, and the amount of tritium in thelysate was measured using a liquid scintillation counter to determine[³H]dopamine uptake. Non-specific binding of tritium was measured in acontrol reaction containing 10 μM nomifensine, and was subtracted fromthe counts for assays to correct for non-specific binding of tritium.Reduction of [³H]dopamine uptake by 50 percent or more (50%) relative toan uninhibited control reaction indicates significant inhibitoryactivity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. Thereference compound for the assay was nomifensine, for which the IC₅₀value of 11 nM was obtained in a typical experiment.

6.5. Norepinephrine Functional Uptake Assay for Rat Reuptake Transporter

Quantification of norepinephrine uptake was performed using synaptosomesisolated in a 0.32 M sucrose buffer from a male Wistar rat hypothalamus.The uptake of radiolabelled norepinephrine by synaptosomes (100 μg ofproteins/point) was allowed by incubating them for 20 minutes at 37° C.in presence of test compounds and [³H]-norepinephrine (0.1 μCi/point).The experiment was performed in a deep well.

Synaptosomes and [³H]-norepinephrine were prepared in a Krebs buffer pH7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated for 5 minutes before incubation. Basalcontrol was incubated for 20 minutes at 4° C. in order to avoid anyuptake. Following this incubation, the uptake was stopped by filtrationthrough a unifilter 96-wells GFB Packard plate washed with Krebs buffercontaining 25 mM NaHCO₃ in order to eliminate the free[³H]-norepinephrine. The radioactivity associated to the synaptosomesretained onto the unifilter corresponding to the uptake was thenmeasured with a microplate scintillation counter (Topcount, Packard)using a scintillation fluid.

The reference compound was protriptyline tested at 13 concentrationsranging from 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See,Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

6.6. Norepinephrine Functional Uptake Assay for Human ReuptakeTransporter

Inhibition of human norepinephrine reuptake transporter was assayedusing the recombinant human norepinephrine transporter expressed ineither HEK293 or MDCK cells using a published method (Galli A et al., J.Exp. Biol. 198: 2197-2212, 1995). The cells were plated before theassay. Test compound and/or vehicle was preincubated with cells inmodified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C.Following the preincubation, 25 nM [³H]norepinephrine was added for anadditional timed incubation period (10 to 20 minutes). After the cellswere washed to remove [³H]norepinephrine not internalized, the cellswere lysed, and the amount of tritium in the cell lysate was measuredusing a liquid scintillation counter to determine [³H]norepinephrineuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM imipramine (or 10 μM nisoxetine), and wassubtracted from the counts for assays to correct for non-specificbinding of tritium. Reduction of [³H]norepinephrine uptake by 50 percentor more (≧50%) relative to an uninhibited control reaction indicatessignificant inhibitory activity. Compounds were screened at 10, 1, 0.1,0.01 and 0.001 μM. The reference compounds for the assay weredesipramine and nisoxetine, for which 1050 values of 1.9 nM and 5.3 nMrespectively were obtained in typical experiments.

6.7. Results for Monoamine Uptake Assays

The results of the monoamine uptake assays are provided in Table 8,below.

TABLE 8 Summary of Results - In vitro Monoamine Uptake Assays Human RatCmpd. IC₅₀ (nM) IC₅₀ (nM) No. hSERT hNET hDAT rSERT rNET rDAT  73 2240 61 710 15 6  74 19 4 1 30 6 10  27 201 273 150 500 150 95  75 169 85 21110 20 58  76 156 9 1  77 158 19 4 170 E1 1030 189 1190 170 E2 673 26427  78 651 36 2 172 E1 51 4 66 172 E2 89 127 762 174 246 2495 2781 17555 15 125 176 533 612 775 177 3220 84 322  28 4560 1840 707  29 52401480 195  30 4520 >10,000 5870  31 >10,000 >10,000 >10,000  809170 >10,000 >10,000  79 768 270 884 101 96 529 268 102 195 586 420 1001500 6630 3410 103 3540 5090 7740  81 2720 2190 3640  88 829 171 93  89278 63 9  32 949 902 424  87 1470 334 139  82 55 9990 42  83 57 61 57 33 305 232 83  98 >10,000 782 419 105 1530 28 625 107 224 146 546 1049490 516 5160 106 8330 816 1770  34 >10,000 6690 5320  35 >10,000 29704710  36 6550 1630 >10,000  37 >10,000 5760 >10,000  84 1870 326 395  85102 51 26  96 688 137 170  97 31 10 11  95 480 160 324  91 >10,000 85501830  90 839 1850 3360  92 33 206 125  93 34 295 90  94 3 7 3  99 145 2617  86 249 346 384 133 E1 969 217 355 133 E2 342 374 886 134 E1 260 179598 134 E2 1260 132 149 173 1550 277 412  1 1290 175 103  41 898 22 82165 E1 1580 183 66 165 E2 661 620 978 166 E1 176 310 245 166 E2 90 32 99173 E1 1660 1350 388 173 E2 406 174 280  2 543 316 69 169 E2 332 22 87169 E1 1100 242 778 152 E1 405 32 18 152 E2 77 157 585 153 E1 17 19 85153 E2 64 135 25  42 935 280 761 cis 121 >10,000 2060 3390 E1 cis 1213160 6580 >10,000 E2 trans 121 247 303 687 E1 trans 121 8150 392 665 E2 2 E1 406 167 180  2 E2 821 1040 770 108 65 36 85  43 15 7 64  3 331 888<1 109 9674 114 12  4 637 2783 75 110 7932 790 2 111 8571 232 1.7 112299 39 <1 298 >10,000 6730 76 184 E1 >10,000 2977 213 184 E2 >10,0003385 789 187 E1 1896 1095 209 187 E2 376 928 17 116 2060 633 3 117 7903405 33 115 >10,000 41 <1 114 >10,000 1813 16 113 2574 2217 285 185E1 >10,000 >10,000 421 185 E2 >10,000 >10,000 121 190 E1 2962 442 24 190E2 44 17 3 120 340 45 191 E1 2532 747 42 191 E2 426 74 2  45 5936 964 9 46 >10,000 >10,000 349 188 E1 4479 10000 426 188 E2 >10,000 5287 66  44E1 12 10 36 14 2.2 150 cis 167 >10,000 >10,000 2217 trans 167 4912 1092145 168 1465 732 108 253 906 949 37 254 294 19 <1 190 2.4 100  71 12981342 123  72 136 63 1.7 299 3873 2377 720  44 E2 239 570 219 210 44 1800 5 7115 5004 1522 287 1037 335 192 255 1421 2472 170 256 69 39 157 280130 990 288 84 18 22 67 11 370  47 364 2894 5171  48 E2 149 441 297 23074 550  48 E1 81 57 30 54 5.1 170 257 2075 6546 1999 259 5892 1179 665 6 >10,000 >10,000 1000  7 255 3987 527 260 2146 1772 306 261 30 62 7262 >10,000 >10,000 4283 263 674 187 498  8 855 8733 996  9 >10,0009987 >10,000  49 286 9217 739  10 1905 7446 2928 264 1052 194 17  117549 2811 532 265 109 3464 1454 266 168 2811 859  12 1517 5761 6043 1100480 1900  57 1079 3177 1777 2200 740 2300  51 2948 >10,000 >10,000  501069 950 499 cis 124 6857 5934 5313 trans 124 2489 842 1475 E1 trans 124227 288 187 E2  14 2953 257 46 267 1290 3256 147 268 704 241 27 269 78736 <1 300 >10,000 7625 1733 301 >10,000 >10,000 8785 cis 125 684 399 871trans 125 6 158 1408 E1 trans 125 32 783 1113 E2  52 44 1063 176  13 377324 122 194 330 1832 2369 196 1445 732 911 197 227 67 450192 >10,000 >10,000 1957 200 2051 3742 1100 201 261 518 88 204 2253 3457296 205 E1 4208 999 800 205 E2 1714 326 12 cis 132i 708 5555 153 trans132i 28 353 140  15 1398 >10,000 >10,000 206 E1 72 121 59 206 E2 306 7<1 147 E1 94 5764 1391 18 370 1200 147 E2 2500 9706 1344 1700 1200 1500148 E1 97 538 464 36 81 250 148 E2 229 1136 289 330 4900 680  53 <1 20 16.5 2.9 6.1  54 2387 857 85  55 <1 61 72 163 E1 43 2793 413 260 42001100 163 E2 139 2650 309 1900 3200 1500 164 E1 2 152 36 9.6 500 230 164E2 13 194 40 45 720 140 195 E2 45 >10,000 5320 270 469 515 376 271 79 42197 289 469 1467 282 290 992 >10,000 1388  17 657 119 29  16 1764 40344085  13 E1 187 528 66  18 3892 794 184  19 107 3177 2316  13 E2 60 779108  56 E1 <1 21 28 2.9 2.3 24  56 E2 63 468 145 120 79 100 272 >10,0009572 2601 273 830 474 528 274 809 321 251 275 1187 943 518 276 210 55 71360 17 190 277 34 13 41 42 2.7 43  58 E1 6 23 63 9.5 3.6 22  58 E2 118341 176 100 33 160 140 E1 2688 >10,000 8819 140 E2 >10,000 >10,000 5667139 E1 >10,000 >10,000 >10,000 139 E2 >10,000 >10,000 >10,000  20 245847 275  20 E1 40 6439 369  20 E2 60 >10,000 437  21 2095 7192 43 207142 3602 1025 209 1158 >10,000 4758 222 609 5347 2090 225 7 23 167 22373 145 874  22 296 3727 141 155 E1 2986 >10,000 >10,000 155 E26281 >10,000 >10,000 136 E1 >10,000 6497 2871 136 E2 >10,000 >10,0003375 138 E1 >10,000 1341 918 138 E2 6996 3946 2539  21 E1 9661 7606 234 21 E2 1235 6041 64 193 E2 957 >10,000 3163 193 E1 416 897 266 1982324 >10,000 1940 202 868 1625 58 199 2188 2585 462 203 56 166 1.4 156E1 76 >10,000 1310 156 E2 653 >10,000 3996 226 44 737 278  23 62 7678682  22 E1 63 2624 136  22 E2 101 5566 112 208 1987 >10,000 7667 227 7424103 5778 228 96 387 1565 229 11 33 40 224 69 665 993 154 E1 2170 3679795 154 E2 439 981 888 16 E1 1755 1291 1286 16 E2 7296 1910 9248 211 551274 195 230 30 104 11 231 E1 1276 136 460 231 E2 63 19 83 291 185 78472 212 91 948 75 213 283 2031 337  17 E1 355 66 71  17 E2 709 93 5  60E1 184 86 748  60 E2 4632 3304 6740  61 E1 5947 1504 959  59 E2 43962197 3875  59 E1 1589 486 1754  61 E2 9442 1555 116 293 42 33 4 232 744904 25 233 37 64 3  62 E1 3176 414 39  62 E2 4241 121 4  19 E1 1514 1901696  19 E2 398 4027 735 234 E1 3382 820 346 234 E2 18 33 21  63 E2 21110 1818  64 E1 58 2797 >10,000  64 E2 32 2647 3640  63 E1 194 59466537 235 9 256 92 292 360 903 89 236 38 718 444  38 472 >10,000 9647  651618 3644 1936  66 221 587 355 278 5143 >10,000 3193 279 383 2477 1449280 7 371 242  25 78 1029 90  26 740 2102 238 214 >10,000 10000 >10,000237 7296 >10000 9129 238 1178 3533 5715 215 4192 >10000 6243 239 86617372 9451 240 1812 3694 9029  39 295 6644 2237  67 230 3149 1761  68 19603 343 294 >10,000 >10,000 >10,000 281 256 788 384 282 296 289 186 28320 41 37 216 >10,000 >10,000 >10,000 241 >10,000 >10,000 >10,000 2427656 >10,000 >10,000 295 >10,000 >10,000 >10,000 217 47 1838 1975 243 26293 851 244 14 59 334  24 364 6380 1370 141 E1 3687 2229 1252 141 E22771 10000 3665 142 E1 1898 >10,000 5247 142 E2 2315 >10,000 7852 218480 >10,000 5587 245 538 10000 2274 246 43 984 282  40 753 7668 2324  69930 2290 605  70 29 261 214 157 E1 1303 3725 575 157 E2 290 3446 849 158E1 8439 7497 945 158 E2 2991 >10,000 5023 145 E1 75 10000 4726 145 E2220 >10,000 6520 146 E1 4545 >10,000 >10,000 146 E2 2284 >10,000 >10,000219 269 >10,000 >10,000 247 707 9690 10000 248 159 5689 7252 220 615010000 >10,000 249 405 >10,000 >10,000 250 47 1669 10000 284 7896 66622462 285 1139 4038 1897 286 46 182 198 162 E2 247 >10,000 >10,000 162 E1495 >10,000 >10,000 161 E2 1.1 4395 4609 161 E1 9 8626 9950 221 61 5825182 251 199 2131 107 252 11 108 6 252 12 134 5 143 E1 8611 >10,000 8787143 E2 7172 >10,000 8630 144 E1 5626 >10,000 10000 144 E2 8748 >10,0009858 159 E1 1255 >10,000 3801 159 E2 42 10000 2310 160 E1 7193 >10,0009725 160 E2 5091 >10,000 >10,000 296 73 87 27 297 40 57 13

In Table 8, compound numbers correspond to those used in the Examplesabove. In addition, the following abbreviations have been used in TableI: SERT (serotonin transporter), NET (norepinephrine transporter) andDAT (dopamine transporter).

The above results indicate that compounds of the invention exhibitpotent inhibition of neuronal uptake of NE, DA, and/or 5-HT, and comparefavorably with potencies seen for various existing therapeutic agents.For example, reported potencies (IC₅₀ or K_(i) values) of approved andlaunched drugs include: fluoxetine (PROZAC®), 7 nM for inhibition ofhuman 5-HT reuptake transporter; methylphenidate (RITALIN®), 193 nM and38 nM for inhibition of human dopamine and norepinephrine reuptaketransporters, respectively (Eshleman et al., J. Pharmacol. Exp. Ther.1999, 289: 877-885); amitriptyline (ELAVIL®), 63 nM and 67 nM forinhibition of the human norepinephrine and serotonin reuptaketransporters, respectively and venlafaxine (EFFEXOR®, a so-calledserotonin norepinephrine reuptake inhibitor (SNRI) 145 and 1420 nM, forinhibition of the human serotonin, and norepinephrine reuptaketransporters respectively (Vaishnavi et al., Biol. Psychiatry. 2004, 55:320-322). The multiple inhibition of the neuronal uptake of NE, DAand/or 5-HT displayed by the compounds of the invention provides theclinician with the ability to more effectively treat CNS disorders,including without limitation affective disorders, cerebral functiondisorders, anxiety disorders, neuropathic pain, and migraine or migraineheadache, by elevating various monoamine levels in the brainsimultaneously and over the same dose-range without the need to titrateseparate drugs.

Example 7 Ex Vivo Binding Assays

Receptor occupancy of central noradrenaline (NA), 5-HT and dopamine (DA)transporter sites following peripheral administration of compounds wasdetermined using [³H] nisoxetine, [³H] citalopram and [³H] WIN 35428binding, respectively. Liquid scintillation counting was used toquantify the radioactivity.

7.1. Methods

C57BL/6 mice (25-30 g) were dosed orally with either vehicle or compoundat 4 dose levels. Mice were sacrificed 60 minutes after treatment. Wholebrains were removed and cortex and striata dissected out before beingfrozen on dry ice. The brain tissue was stored at −20° C. until the dayof the assay. The cortex from each hemisphere was frozen separately. Onewas used to determine occupancy of NA transporter sites and the otheroccupancy of 5-HT transporter sites. Striatum was used to determineoccupancy of DA transporter sites.

7.2. Membrane Preparation

Frontal cortex from each hemisphere or striata was homogenisedindividually in ice-cold assay buffer using a tight fitting glass/Teflonhomogeniser and used immediately in the binding assay.

[³H] Citalopram Binding to 5-HT Transporter (SERT) Sites in Mouse Brain

Cortical membranes (400 μl; equivalent to 1.25 mg wet weight oftissue/tube) were incubated with 50 μl of [³H] citalopram at a singleconcentration of 1.3 nM and either 50 μl of buffer (total binding) or 50μl of paroxetine (0.5 μM; non-specific binding) for 1 h at 27° C. Foreach animal, three tubes were used for the determination of totalbinding and three tubes were used for the determination of non-specificbinding.

[³H] Nisoxetine Binding to Norepinephrine Transporter (NET) Sites inMouse Brain

Cortical membranes (400 μl; equivalent to 6.0 mg wet weight oftissue/tube) were incubated with 50 μl of [³H] nisoxetine at a singleconcentration of 0.6 nM and either 50 μl of buffer (total binding) or 50μl of mazindol (1 μM; non-specific binding) for 4 h at 4° C. For eachanimal, three tubes were used for the determination of total binding andthree tubes were used for the determination of non-specific binding.

[³H] WIN 35428 Binding to DA Transporter (DAT) Sites in Mouse Brain

Striatal membranes (200 μl; equivalent to 2 mg wet weight oftissue/tube) were incubated with 25 μl of [³H] WIN 35428 at a singleconcentration of 24 nM and either 25 μl of buffer (total binding) or 25μl of GBR12935 (1 μM; non-specific binding) for 2 h at 4° C. For eachanimal, two tubes were used for the determination of total binding andtwo tubes for the determination of non-specific binding.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Skatron 11731 filters, presoaked in 0.5% PEI, using a Skatroncell harvester. Filters were rapidly washed with ice-cold phosphatebuffer and radioactivity (dpm) was determined by liquid scintillationcounting (1 ml Packard MV Gold scintillator).

7.3. Data Analysis

A value for specific binding (dpm) was generated by the subtraction ofmean non-specific binding (dpm) from mean total binding (dpm) for eachanimal. Data are presented as mean specific binding (dpm) and as apercentage of the vehicle-treated control taken as 100%.

7.4. Results Summary

Ex vivo SERT, NET and DAT binding/receptor occupancy data were generatedfor selected compounds of the invention. Results are summarized in Table9, below. Results showed that the compounds exhibited varying SERT, NETand DAT inhibition ratios.

TABLE 9 Ex Vivo Binding Profile in Mice. Treatment Mean Specific Binding(dpm) ± S.E.M. Dose (Values in Brackets Denote % Transporter Occupancy)(mg/kg, PO) NET SERT DAT 225 0 1570 ± 31 4639 ± 294 20453 ± 2500 1 1170± 68 (25)* 3842 ± 152 (17)* 19787 ± 3338 (3) 3  813 ± 64 (48)* 2118 ±139 (54)* 21666 ± 3698 (−6) 10  393 ± 21 (75)*  904 ± 35 (81)* 18872 ±2775 (8) 30  230 ± 33 (85)*  414 ± 37 (91)* 14618 ± 1209 (29)  48 E1 02405 ± 150 4345 ± 123 20378 ± 1315 1 2111 ± 119 (12) 4398 ± 39 (−1)20656 ± 1531 (−1) 3 1911 ± 144 (21)* 3957 ± 224 (9) 18039 ± 1265 (11) 10 954 ± 115 (60)* 2796 ± 100 (36)*  9792 ± 977 (52)* 30  346 ± 55 (86)*1003 ± 104 (77)*  3173 ± 541 (84)* 276 0 1541 ± 87 4269 ± 299 15011 ±2450 1 1602 ± 51 (−4) 3743 ± 199 (12) 18155 ± 2275 (−21) 3 1631 ± 92(−6) 3685 ± 292 (14) 16312 ± 2396 (−9) 10 1553 ± 27 (−1) 3092 ± 207(28)* 15879 ± 2265 (−6) 30 1138 ± 59 (26)* 1558 ± 169 (64)* 10397 ± 931(31)  58 E1 0 1763 ± 45 3410 ± 200 16873 ± 1162 1 1705 ± 71 (3) 3245 ±107 (5) 15732 ± 1360 (7) 3 1748 ± 56 (1) 3021 ± 182 (11) 14938 ± 2613(11) 10 1262 ± 79 (28)* 1799 ± 115 (47)* 17215 ± 2151 (−2) 30  502 ± 36(71)*  469 ± 43 (86)* 12876 ± 2152 (24) 153 E2 0 1915 ± 57 3223 ± 10920775 ± 1607 1 1804 ± 79 (6) 3271 ± 199 (−1) 22774 ± 916 (−10) 3 1726 ±44 (10) 2968 ± 100 (8) 24159 ± 1313 (−16) 10 1734 ± 62 (9) 2327 ± 150(28)* 22015 ± 1912 (−6) 30 1140 ± 53 (40)* 1359 ± 89 (58)* 16194 ± 1293(22) 164 E1 0 1040 ± 76 3504 ± 223 21321 ± 1994 1 1122 ± 58 (−8) 2796 ±133 (20)* 23574 ± 1313 (−11) 3 1046 ± 23 (−1) 2273 ± 74 (35)* 18002 ±1516 (16) 10  903 ± 48 (13)  783 ± 61 (78)* 17727 ± 2871 (17) 30  610 ±59 (41)  271 ± 50 (92)* 15630 ± 1085 (27) 56 E1 0  767 ± 34 3326 ± 7843705 ± 2192 1  616 ± 50 (20)* 2625 ± 138 (19)* 41561 ± 1611 (5) 3  368± 17 (52)* 1346 ± 109 (58)* 42127 ± 2130 (4) 10  106 ± 20 (86)*  278 ±42 (91)* 33478 ± 1779 (23)* 30  19 ± 2 (98)*  151 ± 60 (95)* 14637 ±1567 (67)* 277 0 1007 ± 16 1423 ± 120 43023 ± 2628 1  950 ± 46 (6) 1508± 86 (−6) 35827 ± 2302 (17) 3  824 ± 30 (18)* 1491 ± 75 (−5) 34136 ±4104 (21) 10  533 ± 25 (47)* 1416 ± 43 (0) 33230 ± 2807 (23) 30  294 ±42 (71)* 1384 ± 101 (3) 31743 ± 4406 (26) *p < 0.05, vs. vehicle (0);One Way ANOVA

Example 8 In Vivo Analyses 8.1. Rat Forced Swim Test

The method, which detects antidepressant activity, followed thatdescribed by Porsolt et al (Eur. J. Pharmacol., 47, 379-391, 1978) andmodified by Lucki et al. (Psychopharm., 121, 66-72, 1995). Rats forcedto swim in a situation from which they cannot escape rapidly becomeimmobile. Antidepressants decrease the duration of immobility. Inaddition, distinct patterns of active behaviors are produced byantidepressants that selectively inhibit norepinephrine (NE) andserotonin (5-HT) uptake in this test. Selective NE reuptake inhibitorsdecrease immobility by increasing climbing behaviors whereas selective5-HT reuptake inhibitors decrease immobility by increasing swimmingbehaviors.

Rats were individually placed in a cylinder (Height=40 cm; Diameter=20cm) containing 22 cm water (25° C.) for 15 minutes on the first day ofthe experiment (Session 1) and were then put back in the water 24 hourslater for a 5 minute test (Session 2). The sessions were videotaped andduration of immobility as well as swimming and climbing behaviors duringthe 5 minute test were measured. Twelve rats were tested in each group.The test was performed blind. Compounds were typically evaluated at 3doses (1-30 mg/kg), administered orally 2 times: 24 hours and 30-60minutes before the test (Session 2), and compared with a vehicle controlgroup. Desipramine (20 mg/kg i.p.), administered under the sameexperimental conditions, was used as the positive reference substance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect will be consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m).

8.2. Mouse Tail Suspension Test

The method, which detects antidepressant activity, follows thatdescribed by Stéru et al (Psychopharmacology, 85, 367-370, 1985).Rodents, suspended by the tail, rapidly become immobile. Antidepressantsdecrease the duration of immobility.

The behavior of the animal was recorded automatically for 5 minutesusing a computerized device (Med-Associates Inc.) similar to thatdeveloped by Stéru et al (Prog. Neuropsychopharmacol. Exp. Psychiatry,11, 659-671, 1987). Ten to twelve mice were tested in each group. Thetest was performed blind. Compounds were typically evaluated at 3 doses(1-30 mg/kg), administered orally one time: 30-60 minutes before thetest, and compared with a vehicle control group. Desipramine (100mg/kg), administered under the same experimental conditions, was used asthe positive reference substance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect was consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m).

8.3. Locomotor Activity

In order to ensure effects of the compounds on immobility time were notrelated to a general stimulant effect on baseline motor activity,locomotor activity was assessed using photocell monitored cages(Med-Associates Inc.). Each test chamber was equipped with infraredphotocell beams to measure movement of the animals. Horizontal andvertical activity were measured.

Rats or mice were pretreated with vehicle or test compounds and placedback in home cage, following which they will be individually placed inlocomotor cages and activity was monitored in 5 minute intervals for upto 60 min.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect was consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m).

8.4. Result Summary

Selected compounds of the invention were evaluated in the mouse tailsuspension and locomotor activity test (Table 10). Results showed thatall tested compounds exhibited an antidepressant-like profile (i.e.,significantly decreased immobility time) with MED's in the range of 3-30mg/kg, PO. At doses active in the tail suspension test, no change or adecrease in baseline motor activity was observed indicating thatantidepressant-like activity was not due to a general stimulant effect.

Selected compounds of the invention were also evaluated in the ratforced swim and locomotor activity tests (Table 11). All testedcompounds exhibited antidepressant-like effects with MED's in the rangeof 10-30 mg/kg, PO. The decrease in immobility produced by thesecompounds appeared to be due to increases in swimming and climbingbehaviors indicative of mixed transporter activity (i.e., SNRIprofiles). In conclusion, the tested compounds of the inventionexhibited an anti-depressant profile in at least three animal models,the mouse tail suspension test and rat locomotor activity test as wellas the rat forced swim test.

TABLE 10 Mouse Tail Suspension and Locomotor Activity Results MouseLocomotor Mouse Tail Suspension Activity Treatment Mean Immobility TotalDistance Dose (mg/kg, PO) Time ± S.E.M. Traveled ± S.E.M.  153 E2 0200.1 ± 5.8 537.2 ± 67.2 3 195.4 ± 7.7 625.5 ± 88.8 10 170.2 ± 6.3*519.5 ± 88.4 30 154.5 ± 8.4* 573.7 ± 63.6  44 E1 0 198.3 ± 7.6 660.0 ±51.6 3 188.9 ± 7.3 576.5 ± 66.9 10 174.5 ± 8.1 721.1 ± 36.5 30 120.4 ±9.0* 402.3 ± 71.0*  93 0 204.6 ± 5.6 494.0 ± 64.1 3 203.5 ± 8.0 644.0 ±55.7 10 185.4 ± 7.9 606.9 ± 72.4 30 162.0 ± 8.1* 737.6 ± 89.5  48 E1 0199.9 ± 6.7 647.7 ± 42.6 3 189.8 ± 7.2 622.5 ± 101.6 10 174.1 ± 5.8*620.0 ± 79.4 30 134.5 ± 9.6* 468.6 ± 114.2 134 E2 0 200.0 ± 6.7 782.8 ±94.2 3 191.4 ± 6.2 862.7 ± 100.4 10 170.8 ± 6.0* 671.6 ± 63.3 30 137.2 ±7.2* 728.2 ± 107.7  75 0 194.2 ± 6.0 659.4 ± 63.1 3 187.8 ± 9.6 653.5 ±48.4 10 177.7 ± 5.8 608.8 ± 83.4 30 143.5 ± 5.8* 655.3 ± 117.7 148 E1 0207.6 ± 7.8 445.7 ± 71.5 3 193.7 ± 6.0 584.8 ± 65.7 10 189.3 ± 5.9 486.3± 74.3 30 174.5 ± 5.0* 559.6 ± 88.2 225 0 195.1 ± 4.1 735.2 ± 54.5 0.3188.1 ± 8.0 519.5 ± 56.4* 1 186.5 ± 5.2 423.4 ± 62.3* 3 158.5 ± 4.9*415.9 ± 61.6* 225 0 192.5 ± 6.3 336.6 ± 77.5 3 155.2 ± 6.0* 341.8 ± 78.310 137.8 ± 5.2* 234.2 ± 49.4 30 136.3 ± 2.5* 177.4 ± 47.8 164 E1 0 197.3± 7.0 509.4 ± 92.7 3 183.8 ± 6.5 377.8 ± 67.6 10 162.1 ± 4.6* 210.3 ±40.4* 30 155.3 ± 7.8* 494.0 ± 84.9  56 E1 0 203.6 ± 4.5 439.6 ± 63.5 3184.0 ± 4.8 410.2 ± 89.3 10 174.8 ± 6.1* 440.2 ± 62.6 30 141.9 ± 7.4*252.2 ± 55.8 277 0 199.8 ± 6.1 378.9 ± 45.2 3 182.3 ± 8.1 418.8 ± 80.610 164.4 ± 6.8* 411.8 ± 87.8 30 147.1 ± 3.1* 327.7 ± 67.1 276 0 202.7 ±6.3 565.9 ± 104.3 3 182.0 ± 4.2 625.9 ± 47.5 10 164.1 ± 5.7* 382.4 ±63.4 30 160.2 ± 7.2* 607.8 ± 57.8 164 E2 0 184.6 ± 10.1 520.4 ± 103.8 3181.8 ± 6.3 518.2 ± 106.1 10 179.1 ± 4.5 464.5 ± 86.2 30 141.8 ± 6.0*669.9 ± 75.6  17 E1 0 197.3 ± 5.6 463.0 ± 73.4 3 184.7 ± 9.0 649.3 ±78.4 10 182.6 ± 4.1 478.3 ± 88.5 30 150.9 ± 7.8* 428.3 ± 120.6 *p <0.05, vs. vehicle (0); One Way ANOVA

TABLE 11 Rat Forced Swim and Locomotor Activity Results Rat LocomotorActivity Treatment Rat Forced Swim (Means ± S.E.M.) Total Distance Dose(mg/kg, PO) Immobility Swimming Climbing Traveled ± S.E.M.  48 E1 0 48.0± 2.1 4.8 ± 1.2 7.0 ± 1.5 1480.0 ± 67.4 3 49.6 ± 1.5 3.7 ± 1.0 7.1 ± 0.61869.9 ± 188.4 10 35.6 ± 3.5* 6.5 ± 1.6 17.9 ± 2.5* 1825.3 ± 109.3 3026.9 ± 4.4*  9.7 ± 1.7* 20.6 ± 2.9* 1840.6 ± 56.6 153 E2 0 50.8 ± 1.81.0 ± 0.3 8.2 ± 1.8 1685.1 ± 106.8 3 49.9 ± 1.7 1.9 ± 0.8 8.8 ± 1.51577.8 ± 80.1 10 44.0 ± 2.1  4.3 ± 1.1* 11.7 ± 1.8  1994.2 ± 263.9 3031.3 ± 6.7*  4.6 ± 1.3* 22.2 ± 5.2* 2033.7 ± 215.4  93 0 48.5 ± 1.4 3.7± 0.7 7.8 ± 1.1 1682.2 ± 66.8 3 44.5 ± 2.5 6.5 ± 1.6 9.0 ± 1.3 1802.6 ±150.6 10 41.4 ± 2.8 6.9 ± 1.3 12.8 ± 2.2  1641.0 ± 144.5 30 25.8 ± 5.4*12.0 ± 2.1* 22.2 ± 3.5* 2095.6 ± 147.2 277 0 46.5 ± 2.9 1.2 ± 0.6 12.1 ±2.7  1586.0 ± 191.3 3 50.4 ± 1.1 0.8 ± 0.3 9.0 ± 1.2 1406.2 ± 84.9 1042.5 ± 2.6  3.7 ± 0.9* 13.8 ± 2.3  1861.4 ± 187.8 30 14.6 ± 3.5*  6.1 ±1.4* 35.6 ± 5.2* 2612.4 ± 210.8* 225 0 52.4 ± 1.8 0.8 ± 0.4 6.8 ± 1.81610.3 ± 101.1 3 50.8 ± 1.8 0.8 ± 0.3 8.4 ± 1.7 1783.4 ± 182.7 10 47.6 ±3.0 1.2 ± 0.6 11.1 ± 2.7  1628.5 ± 159.2 30 33.4 ± 4.8* 1.1 ± 0.5 25.0 ±4.6* 2182.8 ± 151.2*  56 E1 0 53.8 ± 0.6 0.4 ± 0.2 5.8 ± 0.7 1272.6 ±113.2 3 52.2 ± 1.6 0.3 ± 0.2 7.1 ± 1.6 1227.9 ± 84.4 10 50.7 ± 1.0 0.8 ±0.3 8.6 ± 0.9 1230.8 ± 64.8 30 40.4 ± 2.7* 1.0 ± 0.4 17.9 ± 2.4* 1359.8± 132.7 *p < 0.05, vs. vehicle (0); One Way ANOVA

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

What is claimed is:
 1. A compound having a structure according to Formula (I):

wherein n is an integer from 0 to 2; s is an integer from 1 to 3; m is an integer from 0 to 12, with the proviso that when n is 0, then m is not greater than 8; and when n is 1, then m is not greater than 10; Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system; each X is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein each R⁵, R⁶ and R⁷ is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein two of R⁵, R⁶ and R⁷, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring; each R¹ and R² is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR^(B), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R⁸ is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and R³ and R⁴ are members independently selected from the group consisting of H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, N═N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, with the proviso that when one member of R³ and R⁴ is N═N, then the other member is not present, wherein R⁹ is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; wherein at least two of R¹, R², R³, R⁴ and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring; at least one of R¹, R², R³ and R⁴ is optionally joined with Ar to form a 5- to 7-membered ring; and any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.
 2. The compound according to claim 1, wherein said compound is chiral.
 3. The compound according to claim 1 having a Formula, which is a member selected from the group consisting of Formula (II) and Formula (III):


4. The compound according to claim 3, said compound having a Formula, which is a member selected from the group consisting of:

wherein X¹ and X² are members independently selected from the group consisting of H, OR⁵, SR⁵, halogen, CN, CF₃, S(O)₂R⁵, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, acyl, substituted or unsubstituted C₁-C₄ alkyl and substituted or unsubstituted C₁-C₄ heteroalkyl, wherein at least two of R¹, R³, R⁴, X¹ and X², together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
 5. The compound according to claim 4, wherein X′ and X² are members independently selected from the group consisting of H, methyl, ethyl, n-propyl, OH, OMe, OEt, F, Cl, CN, CH₂OH, CH₂OMe, and CF₃.
 6. The compound according to claim 4, wherein R¹ is H or substituted or unsubstituted C₁-C₄ alkyl.
 7. The compound according to claim 4, wherein R³ and R⁴ are members independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
 8. The compound according to claim 3, wherein Ar is a member selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl.
 9. The compound according to claim 8, wherein Ar has a structure, which is a member selected from the group consisting of:

wherein Y, Z, Y¹ and Z¹ are members independently selected from the group consisting of H, halogen, CF₃, CN, OR¹¹, SR¹¹, NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, S(O)₂R¹¹, acyl, C(O)OR¹¹, C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, wherein two of Y, Z, Y1 and Z1, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring; and each R¹¹, R¹² and R¹³ is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, wherein two of R¹¹, R¹² and R¹³, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
 10. The compound of claim 9, wherein Y, Z, Y¹ and Z¹ are members independently selected from the group consisting of H, CF₃, OR¹¹, SR¹¹, OCF₃, halogen and CN.
 11. The compound of claim 9, wherein Ar has the structure:


12. A composition comprising a first stereoisomer and at least one additional stereoisomer of a compound according to claim 1, wherein said first stereoisomer is present in a diastereomeric excess of at least 80% relative to said at least one additional stereoisomer.
 13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 14. A method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim
 1. 15. A method of inhibiting the activity of at least one monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim
 1. 16. The method of claim 14 or 15, wherein said monoamine transporter is a member selected from the group consisting of serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET) and combinations thereof.
 17. The method of claim 15, wherein said compound inhibits the activity of at least two different monoamine transporters.
 18. A method of inhibiting uptake of at least one monoamine by a cell, said method comprising contacting said cell and a compound of claim
 1. 19. The method of claim 18, wherein said monoamine is a member selected from the group consisting of serotonin, dopamine, norepinephrine and combinations thereof.
 20. The method of claim 18, wherein said compound inhibits uptake of at least two different monoamines.
 21. The method of claim 18, wherein said cell is a neuronal cell.
 22. A method of treating depression by inhibiting the activity of at least one monoamine transporter, said method comprising administering to a mammalian subject a compound of claim
 1. 23. The method of claim 22, wherein said mammalian subject is a human.
 24. The method of claim 22, wherein said compound inhibits said activity of at least two different monoamine transporters.
 25. A method of treating a central nervous system disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim
 1. 26. The method of claim 25, wherein said subject is a human.
 27. The method of claim 25, wherein said central nervous system disorder is a member selected from the group consisting of depression, cognitive deficit, fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, premenstrual dysphoria, and neurodegenerative disease.
 28. The method according to claim 27, wherein said depression is a member selected from the group consisting of major depressive disorder (MDD), unipolar depression, bipolar disorder, seasonal affective disorder (SAD) and dysthymia.
 29. The method according to claim 27, wherein said neurodegenerative disease is Parkinson's disease.
 30. The method according to claim 27, wherein said sleep disorder is sleep apnea.
 31. The method according to claim 27, wherein said pain is neuropathic pain.
 32. A compound having a structure, which is a member selected from the group consisting of:

wherein n is an integer from 0 to 2; p is an integer from 0 to 2; m is an integer from 0 to 12, with the proviso that when n is 0, then m is not greater than 8; and when n is 1, then m is not greater than 10; Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system; each X is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein each R⁵, R⁶ and R⁷ is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein two of R⁵, R⁶ and R⁷, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring; each R¹ and R² is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁸, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R⁸ is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and wherein at least two of R¹, R² and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring; at least one of R′ and R² is optionally joined with Ar to form a 5- to 7-membered ring; and any salt form, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.
 33. The compound of claim 32, wherein p is
 0. 